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Further investigations on the use of Camphor as an Enantiopure starting material in natural product synthesis Wong, Michael Kay Chung 1996

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Further Investigations on the Use of Camphor as an Enantiopure Starting Material in Natural Product Synthesis by M I C H A E L K A Y C H U N G W O N G B.Sc. (Honours), The University of British Columbia, 1988 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Department of Chemistry) We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA March, 1996 ©Michael K.C. Wong, 1996 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of Chemistry The University of British Columbia Vancouver, Canada Date 31 May 19% DE-6 (2/88) Abstract The use of (-)-camphor (ent-9) as an enantiopure intermediate in pseudoguaianolide and limonoid synthesis and further aspects of the chemistry df 4-methylcamphor (87) are presented in this thesis. First, the preparation of relay compounds ketal-enone 140, hydroxy-ketone 123, hydroxy-enone 158, and hydroxy-ketone 128 represents a formal, enantiospecific synthesis of the helenanolides carpesiolin (96), helenalin (95), bigelovin (97), mexicanin I (98), and linifolin A (99) and the ambrosanolides damsin (102) and confertin (103). (-)-Camphor (ent-9) was converted in nine steps to ketal-ester 164b. Stereoselective alkylation of 164b with methyl iodide yielded ketal-ester 165 that could be elaborated to the ketal-enone 140 in seven steps. Hydroxy-ketone 123 was obtained from 140 in a further three steps. Similarly, stereoselective alkylation of 164b with allyl bromide yielded ketal-ester 184 that could be converted subsequently to hydroxy-enone 158 in nine steps. Finally, catalytic hydrogenation of 158 provided hydroxy-ketone 128. Secondly, as part of an enantiospecific synthetic approach to the limonoids, the tricyclic enone 257 was prepared. (-)-Camphor (ent-9) was converted to the known bicyclic enone-ester (ent-255) in ten steps. Alkylation of ketal-ester .262, derived from ent-255, with methyl bromoacetate yielded ketal-diester 263, which could be transformed into dimethoxy-enone 267 in three steps. Two successive alkylations of enone 267 yielded the j3,^unsaturated enone 279, and subsequent desilylation, oxidation, and aldol condensation steps provided the tricyclic enone 257, which has potential as a BCD-intermediate for the synthesis of tetracyclic limonoids. Finally, a proposed mechanism for the bromination of endo-3-bromo-4-methylcamphor (327) to yield e«do-3,9-dibromo-4-(bromomethyl)camphor (332) was evaluated using the corresponding deuterium-labelled analogue, e«do-3-bromo-9-deuterio-4-(deuteriomethyl)cam-phor (351), as substrate. NMR spectroscopic evidence was used to identify the product resulting from the bromination of 351 as g«rfo-3,9-dibromo-9-deuterio-4-(bromodeuteriomethyl)camphor (352). Evidence supporting the proposed existence of unsaturated intermediates 355 and 358 in the bromination mechanism was also obtained. Table of Contents Abstract ii Table of Contents iv List of Schemes vii List of Figures x List of Tables x Index of Experimental Procedures xi List of Abbreviations xii Acknowledgements xv Chapter 1: Synthesis of Enantiopure Compounds and Use of Camphor as Enantiopure Starting Material in Natural Product Synthesis (a) The Synthesis of Enantiopure Compounds 2 i. Introduction 2 ii. Access to Enantiomerically Pure Compounds 3 (b) Use of Camphor as an Enantiopure Starting Material in Natural Product Synthesis 7 i. Introduction 7 ii. C(10) Substitution: Camphor-10-Sulfonic Acid, (14), etc 8 iii. C(9) Substitution: Camphor-9-sulfonic Acid (23) and 9-Bromocamphor (24) 10 iv. C(9,10) Disubstitution: 9,10-Dibromocamphor and Intermediates Derived from the Ring-Cleavage of 9,10-Dibromocamphor 13 v. C(8) Substitution: 8-Bromocamphor (38) 15 vi. C(5) Substitution: 5-Bromocamphor (53), 5-Keto-bornyl Acetate (59), and 5-Ketoisobornyl 5 Acetate (62) 18 VII. C(6) Substitution: 6-Bromocamphor (66) and 5,6-Dehydrocamphor (56) 20 VIII. C(3) Substitution: Camphorquinone (55) 24 ix. C(4) Substitution: 4-Methylcamphor (87) 26 x. Cleavage of the C(2)-C(3) Bond of Camphor 27 Chapter 2: A Formal, Enantiospecific Synthesis of Pseudoguaianolides (a) Introduction 29 (b) Previous Synthetic Routes to Pseudoguaianolides 30 (c) An Enantiospecific Synthesis of Helenanolides 40 (d) An Enantiospecific Synthesis of Ambrosanolides 52 Chapter 3: An Enantiospecific Synthetic Approach to the Limonoids (a) Introduction 64 (b) Previous Synthetic Routes to Limonoids and Analogues 67 (c) Results and Discussion 72 i. Preparation of Bicyclic Enone 267 from (-)-Camphor (ent-9) 72 ii. Preparation of Tricyclic Enone 257 from Bicyclic Enone 267 77 iii. Future Directions ....83 Chapter 4: Further Studies on the Chemistry of 4-Methylcamphor: A Multiple Rearrangement Process in the Bromination of cndo-3-bromo-4-methylcamphor (a) Introduction 86 (b) Previous Synthetic Routes to Euphanes, Tirucallanes, Lanostanes, and 14-Methyl Steroids 86 (c) The Proposed Use of 4-Methylcamphor in Triterpenoid and Steroid Synthesis 93 (d) Results and Discussion 96 i. Preparation of 4-Methylcamphor (87), endo-3-BTomo-4-methylcamphor (327), and en Jo-3,9-Dibromo-4-(bromomethyl)camphor (332) 96 //. A Proposed Mechanism for the Bromination of ertdo-3-Bromo-4-methylcamphor (327) 101 iii. Evaluation of the Proposed Bromination Pathway Using e/iJo-3-Bromo-9-deuterio-4-(deuterio-methyl)camphor (351) as a Labelled Substrate 106 iv. Future Directions 119 vi Chapter 5: Experimental Section (a) General Experimental 121 (b) Safety Considerations 123 (c) Experimental Procedures 123 References and Notes 207 Appendix: Supplementary Experimental Procedures 221 List of Schemes CHAPTER 1 Scheme 1.1: Examples of Common Asymmetric Synthetic Methods 6 Scheme 1.2: Preparation of C(10)-Substituted Derivatives of Camphor 8 Scheme 1.3: Mechanism for C(10) Sulfonation of Camphor 9 Scheme 1.4: Use of C(10)-Substituted Camphor Derivatives in Natural Product Synthesis 9 Scheme 1.5: Preparation of C(9)-Substituted Derivatives of Camphor 10 Scheme 1.6: Mechanism of C(9) Sulfonation or Bromination of (+)-endo-3-Bromocamphor (20) 11 Scheme 1.7: Use of 9-Bromocamphor (24) in Natural Product Synthesis 12 Scheme 1.8: Preparation of (+)-9,10-Dibromocamphor (33) 13 Scheme 1.9: Base-Promoted Ring Cleavage of (+)-9,10-Dibromocamphor (33) 13 Scheme 1.10: Use of (+)-9,10-Dibromocamphor (33) in Natural Product Synthesis 14 Scheme 1.11: Preparation of (+)-8-Bromocamphor (38) 15 Scheme 1.12: Bromination of (+)-3,3-Dibromocamphor (39): Proposed Mechanism for the Formation of (+)-3,3,8-Tribromo-camphor (40) and Accompanying By-products 16 Scheme 1.13: Use of (+)-8-Bromocamphor (38) in Natural Product Synthesis 17 Scheme 1.14: Preparation of (+)-5-Bromocamphor (53) 19 Scheme 1.15: Preparation and Use of C(5)-Oxygenated Camphor Derivatives in Natural Product Synthesis 20 Scheme 1.16: Preparation of (-)-e/tdo-6-Bromocamphor (66) 21 Scheme 1.17: Mechanism of the Acid-Catalyzed Rearrangement of (+)-endo-3-Bromocamphor (20) to (-)-endo-6-Bromocamphor (66) 22 Scheme 1.18: Preparation and Synthetic Potential of (+)-5,6-Dehydro-camphor (56) 22 Scheme 1.19: Formal, Enantiospecific Approach to (-)-Furodysin and (-)-Furodysinin 23 Scheme 1.20: Use of (+)-5,6-Dehydrocamphor (56) and (-)-5-Methyl-5,6-dehydrocamphor (57) in the Synthesis of Terpenoid Intermediates 24 Scheme 1.21: Use of (+)- and (-)-Camphorquinone in Natural Product Synthesis 25 Scheme 1.22: Preparation fo (-)-4-Methylacamphor (87) from (+)-Camphor 26 Scheme 1.23: Cleavage of the C(2)-C(3) Bond of Camphor; Use of Camphoric Acid (93) in Natural Product Synthesis 27 CHAPTER 2 Scheme 2.1: Structures of Representative Pseudoguaianolides 29 Scheme 2.2: Roberts and Schlessinger: Total Synthesis of (±)-Helenalin (95) 31 Scheme 2.3: Quallich and Schlessinger: Total Synthesis of (±)-Confertin and (±)-Damsin 32 Scheme 2.4: Heathcock et al.: Formal Synthesis of (±)-Helenalin; Total Synthesis of (±)-Confertin 32 Scheme 2.5: Welch and Bryson: Formal Synthesis of (±)-Helenalin and (±)-Confertin 33 Scheme 2.6: Quinkert et al.: Formal, Enantioselective Synthesis of (+)-Confertin 34 Scheme 2.7: Kennedy and McKervey: Formal Synthesis of (±)-Confertin 35 Scheme 2.8: Vandewalle et al.: Total Synthesis of (±)-Carpesiolin 35 Scheme 2.9: Grieco et al: Total Synthesis of (±)-Bigelovin, (±)-Mexicanin I, and (±)-Linifolin A 36 Scheme 2.10: Money et al: An Enantiospecific Synthetic Approach to the Helenanolides 38 Scheme 2.11: Proposed Formal, Enantiospecific Syntheses of Helenanolides and Ambrosanolides Using Camphor as an Enantiopure Starting Material 39 Scheme 2.12: Conversion of (-)-Borneol to (-)-Hydroxy-ester 160 40 Scheme 2.13: Conversion of (-)-Hydroxy-ester 160 to (-)-Ketal-ester 164b 41 Scheme 2.14: Conversion of (-)-Ketal-ester 164b to the Helenanolide Relay Compounds (-)-Ketal-enone 140 and Hydroxy-Ketone 123 43 Scheme 2.15: Stereoselective Alkylation of an Ester Bearing a Stereocenter at the/3 Position 44 Scheme 2.16: Conversion of (-)-Ketal-ester 164b to the Ambrosanolide Relay Compounds Hydroxy-enone 158 and Hydroxy-ketone 128 53 Scheme 2.17: Synthetic Utility of the Wacker Oxidation. Tsuji et al.: Total Synthesis of (±)-19-Nortestosterone (190) 54 Scheme 2.18: Proposed Mechanism of the Wacker Oxidation 55 Scheme 2.19: Competing Aldol Condensation Pathways of Keto-aldehyde 198 60 CHAPTER 3 Scheme 3.1: Structures of Representative Limonoids 65 Scheme 3.2: Proposed Biogenesis of the Limonoids 66 Scheme 3.3: Corey and Hahl: Total Synthesis of (±)-Azadiradione 68 Scheme 3.4: Fernandez Mateos and de la Fuente Blanco: Synthesis of Limonoid Analogues 69 Scheme 3.5: Fernandez Mateos and de la Fuente Blanco: Synthesis of (±)-Pyroangolensolide 70 Scheme 3.6: Lhommet etal.: Synthesis of a Limonoid Intermediate 70 Scheme 3.7: Synthetic Plan for a Proposed Limonoid Synthesis 72 Scheme 3.8: Preparation of Bicyclic (-)-Keto-enone (ent-255) 72 Scheme 3.9: Preparation of Tricyclic Enone (257) from (-)-Enone-ester ent-255 74 Scheme 3.10: Retrosynthetic Analysis of Tricyclic Dienone 257 77 Scheme 3.11: Preparation of l-Iodo-3-(r-butyldiphenylsilyloxy)pentane (270b) 78 Scheme 3.12: Projected Completion of the Limonoid Synthesis 83 CHAPTER 4 Scheme 4.1: Structures of Representative 14-Methyltriterpenoids and 14-Methyl Steroids 86 Scheme 4.2: Johnson et al: Total Synthesis of (±)-Euphol (204) and (±)-Tirucallol 87 Scheme 4.3: Kolaczkowski and Reusch: Synthesis of the (±)-5-ep/-Euphane Ring System 88 Scheme 4.4: Woodward, Barton, et al: Total Synthesis of (±)-Lanosterol (285) 89 Scheme 4.5: van Tamelen and Anderson: Formal, Enantiospecific Synthesis of Lanosterol (285) 90 Scheme 4.6: Corey et al:. Formal, Enantiospecific Synthesis of Lanosterol 91 Scheme 4.7: Bull and Bischofberger: Total Synthesis of a 14a-Methyl Steroid, (±)-3-Memoxy-14-methyl-14a-estra-l,3,5(10)-trien-17-one 92 Scheme 4.8: Comparison of the Proposed Routes to the Euphanes, Tirucallanes, Lanostanes, and 14a-Methyl Steroids to the Hutchinson-Money Synthesis of Estrone 95 Scheme 4.9: Money et al:. Preparation of (-)-4-Methylcamphor (87) from (+)-Camphor 96 Scheme 4.10: Mechanism for the Transformation of (-)-2-Methylenebornane (88) to (+)-4-Methylisobornyl Acetate (89) 97 Scheme 4.11: Money and Palme: Preparation of Enantiopure (-)-4-Methyl-camphor (87) from (+)-Camphor 99 Scheme 4.12: Bromination of 4-Methylcamphor (87) 100 Scheme 4.13: Proposed Reaction Pathway for the Bromination of endo-3-Bromo-4-methylcamphor (327) 103 Scheme 4.14: Comparison of the Bromination of erafo-3-Bromocamphor (20) and ertdo-3-Bromo-4-methylcamphor (327) under Br2/C1SC>3H Conditions 105 Scheme 4.15: Reaction Pathway for the Bromination of e/ufo-3-Bromo-9-deuterio-4-(deuteriomethyl)camphor (351) 106 Scheme 4.16: Conversion of enrfo-3,9-Dibromo-4-(bromomethyl)camphor (332) to 9-Deuterio-4-(deuteriomethyl)camphor (363). Conversion of 9-Deuterio-4-(deuteriomethyl)camphor (363) to Deriva-tives for Use in Investigating the Mechanism of the Bromina-tion of endo-3-Bromo-4-methylcamphor (327) 108 Scheme 4.17: Possible Fates of Carbocation 354 During the Bromination of mio-3-Bromo-9-deuterio-4-(deuteriomethyl)camphor (351) 113 Scheme 4.18: Proposed Use of 4-Methylcamphor and Derivatives as Inter-mediates in Triterpenoid and Steroid Synthesis 119 X List of Figures Figure 4.1: 400 MHz J H NMR Spectrum of endo-3,9-Dibromo-4-(bromo-methyl)camphor (332) 102 Figure 4.2: 400 MHz *H NMR Spectrum of 9-Deuterio-4-(deuteriomethyl-camphor (363) 109 Figure 4.3: 400 MHz lU NMR Spectrum of g«c(o-3,9-Dibromo-9-deuterio-4-(bromodeuteriomethyl)camphor (352) 112 Figure 4.4: 400 MHz *H NMR Spectra of 9-Deuterio-4-(deuteriomethyl)-camphor (363) recorded before (top) and after (bottom) the bromination cycle (cf. Scheme 4.16) 117 List of Tables Table 5.1: Spectral Data from COSY Spectrum of Keto-ester 163b 128 Table 5.2: Spectral Data from COSY Spectrum of Ketal-ester 164b 130 Table 5.3: Spectral Data from HETCOR Spectrum of Ketal-ester 164b 131 Table 5.4: Results of NOE Experiments for Ketal-ester 165 133 Table 5.5: Spectral Data from COSY Spectrum of Ketal-ester 165 133 Table 5.6: Spectral Data from COSY Spectrum of Hydroxy-ketone 178 140 Table 5.7: Results of NOE Experiments for Ketal-enone 140 143 Table 5.8: Spectral Data from COSY Spectrum of Ketal-enone 140 144 Table 5.9: Spectral Data from HETCOR Spectrum of Ketal-enone 140 144 Table 5.10: Spectral Data from COSY Spectrum of Hydroxy-enone 182 147 Table 5.11: Results of NOE Experiments for Ketal-ester 184 150 Table 5.12: Spectral Data from COSY Spectrum of Ketal-ester 184 151 Table 5.13: Spectral Data from COSY Spectrum of Keto-aldehyde 198 159 Table 5.14: Results of NOE Experiments for Hydroxy-ketone 128 164 Table 5.15: Spectral Data from COSY Spectrum of Hydroxy-ketone 128 165 Table 5.16: Spectral Data from HETCOR Spectrum of Hydroxy-ketone 128 166 Table 5.17: Spectral Data from COSY Spectrum of Dimethoxy-enone 267 178 Table 5.18: Results of NOE Experiments for Tricyclic Enone 257 187 Table 5.19: Spectral Data from COSY Spectrum of Tricyclic Enone 257 188 Table 5.20: Results of NOE Experiments for encfo-3,9-Dibromo-4-(bromo-methyl)camphor (332) 197 Table 5.21: Spectral Data from COSY Spectrum of end0-3,9-Dibromo-4-(bromomethyl)camphor (332) 198 Table 5.22: Spectral Data from HETCOR Spectrum of e/ido-3,9-Dibromo-4-(bromomethyl)camphor (332) 198 Table 5.23: Spectral Data from COSY Spectrum of 9-Deuterio-4-(deuterio-methyl)camphor (363) 202 Table A. 1: Spectral Data from COSY Spectrum of Hydroxy-ester 161a 223 Table A.2: Results of NOE Experiments for Hydroxy-ester 161b 224 Table A.3: Spectral Data from COSY Spectrum of Ketal-enone 201 230 Table A.4: Results of NOE Experiments for Ketal-enone 201 230 Index of Experimental Procedures Compound Page Compound Page ent-9 123 196 155 ent-20 124 197 156 ent-22 125 198 157 ent-32 125 199 159 ent-33 125 200 160 ent-2>l 125 201 229 87 192 203 161 88 189 ent-255 170 89 190 257 186 90 191 258 166 123 148 259 168 128 163 261 169 140 142 262 172 158 162 263 173 160 126 264 174 161a,b 222, 224 265 175 162b 126 267 177 163b 127 268 185 164b 129 269 184 165 131 270b 180 170 134 274 179 172 135 275b 179 173 136 277 181 174 137 279 183 178 138 327 193 179 140 328 199 180 141 332 195 181 145 351 202 182 146 352 203 184 149 362 200 185 151 363 201 186 152 364 204 187 154 List of Abbreviations* [a] Q - specific rotation, recorded at the sodium D line (589 nm) at T °C Ac - acetyl [-C(0)CH 3] AIBN - azobis(isobutyronitrile) Anal. - microanalysis A F T - attached proton iest aq. - aqueous Bn - benzyl [C6H 5CH 2-] bp - boiling point Buor/i-Bu - normal-butyl [CH3CH2CH2CH2-] Bz - benzoyl [QHsCCO)-] c - concentration calcd - calculated COSY - correlation spectroscopy. A - unsaturation d - chemical shift D B U - l,8-diazabicyclo[5.4.0]undec-7-ene D C C - dicyclohexylcarbodiimide DCI-MS - desorption chemical impact mass spectrometry or spectrum D E A D - diethyl azodicarboxylate DHP - dihydropyran DIBAL - diisobutylaluminum hydride D M A P - 4-dimethylaminopyridine Abbreviations for chemical elements as well as SI and other units of measurement have been omitted from this list. Definitions of abbreviations and symbols used specifically for the description of nuclear magnetic resonance and infrared spectra are defined in the Experimental section of this thesis (cf. Chapter 5, page 122). xiii D M E - 1,2-dimethoxyethane D M F - N^-m^ethylformamide DMSO - dimethyl sulfoxide e.e. - enantiomeric excess EIMS - electron impact mass spectrometry or spectrum ent - enantiomer of eq - equivalents Et - ethyl [ C H 3 C H 2 - ] G L C - gas-liquid chromatography HETCOR - heteronuclear correlation spectroscopy hfc - 3-(heptafluoropropylhydroxymethylene)-rf-camphorato HMDS - hexamethyldisilazide [((CH3)3Si)2N~] HMPA - hexamethylphosphoramide hv - light /-Pr or Pr' - isopropyl [(CH3>2CH-] IR - infrared (spectroscopy) J - coupling constant L D A - lithium diisopropylamide lit. - literature M - parent mass (mass spectra) or molar, moles per liter (concentration) W J - C P B A - meta-chloroperbenzoic acid mlz - mass-to-charge ratio Me - methyl [ C H 3 - ] M E M - methoxyethoxymethyl [CH3OCH2CH2OCH2-] mp - melting point Ms - mesyl, methanesulfonyl [-SO2CH3] n - normal (nomenclature) NBS - N-bromosuccinimide NMR - nuclear magnetic resonance (spectroscopy) NOE - nuclear Overhauser effect p - para PCC - pyridinium chlorochromate PDC - pyridinium dichromate pet. ether - petroleum ether Ph - phenyl [-C&5] ppm - parts per million PPTS - pyridinium para-toluenesulfonate r.t. - room temperature Rf - retention factor or retardation factor s-Bu or Bus - secondary-butyl [CH3CH2C(CH3)-] t- - tertiary-/-Am - tertiary-amyl t-Bu or Buf - tertiary-butyl [(CH3)3C-] TBAF - tetrabutylammonium fluoride TBAI - tetrabutylammonium iodide TBDMS - remary-butyldimethylsilyl [-Si(CH3)2(C(CH3)3)] TBDPS - rerr/ary-hutyldiphenylsilyl [-Si(C6H5)2(C(CH3)3)] Tf - trifluoromethanesulfonyl [-S02CF3] THF - tetrahydrofuran THP - tetrahydropyranyl Thx - thexyl, tertiary-hexyl [(CH3)2CH-C(CH3)2-] TLC - thin-layer chromatography TMEDA - N^ '^^ '-tetramemylethylenediamine Ts or p-Ts - tosyl, /?ara-toluenesulfonyl Acknowledgments XV Over the course of my graduate studies, I was privileged to have enjoyed the support of many faculty members, fellow graduate students, as well as friends from various undergraduate programs around the University. Unfortunately, space limitations force me to acknowledge, by name, only a subset of these people whom I consider to have made a significance difference to the outcome of my work. First and foremost, I wish to thank my Ph.D. research supervisor, Professor Thomas Money, for his unselfish and enthusiastic support and encouragement. Not only has Tom guided me through the fascinating field of organic chemistry over the last six years, he has taken time to expose me to various professional, academic, and historical aspects of chemistry in general. Tom's commitment to excellence as a teacher and research leader, both at the undergraduate and graduate levels, have strongly influenced my own perspectives on teaching and research. Consequently, I feel privileged to have been part of Tom's research team. I thank the graduate and undergraduate alumni members (1989-1994) of our group for their help. In particular, I thank Scott Richardson (M.Sc, 1994; now at Okanagan University College) for assistance with aspects of the limonoid and steroid projects, and summer students Peter Whitelaw (B.Sc, 1994; now at Capilano College) and Colin Ferguson (B.Sc, 1994; now at Queen's) for technical assistance with various aspects of the 4-methylcamphor projects. Currently, I am fortunate to share my laboratory with two outstanding undergraduate students and friends, Joe Pontillo (B.Sc. thesis researcher; 1996) and Mark K.J. Rushton (B.Sc, 1996). Despite my occasional attempts to 'evict' one of them (!), Mark and Joe have been extremely supportive of my research, teaching, and other endeavors. I thank them for their whole-hearted encouragement and interest and wish them success in their respective graduate careers. I acknowledge Professors Ed Piers and Larry Weiler, both of whom are members of my Ph.D. guidance committee, for their helpful advice and suggestions throughout my graduate career. Additionally, I thank Prof. Piers for taking on the unenviable task of reading my thesis prior to its submission. I am grateful to Dr. Nick Burlinson for helpful discussions on various aspects of NMR spectroscopy. Likewise, I thank my friends Doug Gin (now Prof. Douglas Gin, Berkeley) and Dave Gin (now Dr. David Gin, Harvard) for their advice, criticism, and many helpful discussions. I recall with pleasure that it was Dave, in 1989, who first introduced me to Tom and the wonderful world of camphor chemistry. I extend my gratitude to Messrs. Adam Mezo, Lloyd MacKenzie, and Mark Rushton for voluntarily taking time from own work to proof-read parts of this thesis. The considerable effort and care they took as editors exceeded my expectations, and I very much appreciate their suggestions, ideas, and criticisms. I claim responsibility for any errors or deficiencies that remain. I would also like to acknowledge the Brothers of A A O Fraternity (BC Chapter, 1993-1996) who, despite their diverse individual backgrounds, have been unanimous in their interest in and encouragement of my work. I thank them for making me feel welcome in their organization for nearly three years, and in so doing, convincing me that the Greek system is far more substantial than the image in which it is usually portrayed. Last, but not least, I thank the staff of the NMR Laboratory, Mass Spectrometry Laboratory, Microanalysis Laboratory (Mr. Peter Borda), and Glass Shop (Mr. Steve Rak) for their ongoing assistance; the Chemistry Department for the award of a McDowell Fellowship and a travel grant, as well as for the grant of a Summer Sessional Lectureship to teach C H E M 230 at U B C (1995); the U B C Faculty of Graduate Studies for a travel grant; the Canadian Society for Chemistry for an Organic Division Student Award (1994); and Natural Sciences and Engineering Research Council (NSERC) for the award of a PGS-3 fellowship (1991-1993). I dedicate this thesis to my parents, JohnS.% & Cynthia tttf. "Wong, zuith Cove and thanks for almost thirty years of patience, guidance, and encouragement. Chapter 1 Synthesis of Enantiopure Compounds and Use of Camphor as an Enantiopure Starting Material in Natural Product Synthesis 2 1. Synthesis of Enantiopure Compounds and Use of Cam-phor as an Enantiopure Starting Material in Natural Product Synthesis (a) The Synthesis of Enantiopure Compounds L Introduction In Through the Looking Glass (1872) by Lewis Carroll (1832-1898), Alice wonders about the nature of the world beyond her looking-glass.1 As she is philosophizing, she asks her kitten, "How would you like to live in Looking-glass house, Kitty? I wonder if they'd give you milk in there? Perhaps Looking-glass milk isn't good to drink..." One may be tempted to ask whether Carroll, writing only 24 years after Louis Pasteur (1822-1895) demonstrated the separation of the enantiomers of sodium ammonium tartrate, was aware of the chemical implications of what Alice had just said! In Nature, the majority of natural compounds are biosynthesized in one of two enantiomeric forms, and it is generally recognized now that the two enantiomers of a compound can exhibit completely different biological activities.2 Medicinal chemists often use the term 'eutomer' (from the Greek ev, 'good') to refer to the enantiomer of a drug that gives rise to the desired biological action and the term 'customer' (alternative spelling: dystomer; from the Greek 8v<7-, 'un-') to refer to the alternative enantiomer.3 In addressing the topic of the biological activities of enantiomers one is often reminded of O O H o O H I I (/^-thalidomide (1) (S)-thalidomide (ent-1) (S)-(+)-carvone (fl)-(-)-carvone (2) (ent-1) the tragic example provided by the drug thalidomide (l).2a-3 Thalidomide (1), a bis(imide) bearing a single stereocenter, was commonly administered in the 1950s and early 1960s to pregnant women to combat the effects of morning sickness. Soon after, the high incidence of 3 births of infants with shortened or completely absent limbs prompted regulatory agencies around the world to discontinue the prescription of thalidomide (1). Meanwhile, it was found that although both the (/?)- and (S)- enantiomers of thalidomide (1) possessed the desired sleep-inducing and hypnotic effects, (S)-thalidomide (ent-l) exerted additional embryopathic and teratogenic effects. A less severe illustration of enantiomeric compounds displaying different biological activities is provided by the monoterpenoids (5)-(+)-carvone (2) and (/?)-(-)-carvone (ent-2). Whereas (5)-(+)-carvone (2) tastes of caraway, (/?)-(-)-carvone (ent-2) tastes of spearmint,23 and suggests that our taste receptors are also chiral and can therefore distinguish between enantiomeric compounds. The recognition that different enantiomers of compounds can exert different biological effects prompted the United States Food and Drug Administration to issue a policy statement in 19924 that encourages the production of drugs in enantiomerically pure form. 4 ' 5 Furthermore, in cases where it would be more feasible to develop a drug as a racemate, drug companies would be required to demonstrate that the individual enantiomers were safe. As a result, "... [the drug manufacturers'] recognition of the chiral drug issue persuaded drug firms that were not already doing so [i.e. synthesizing enantiopure drugs] to start developing single enantiomers only." 4 a In fact, so important is the move toward enantiopure drug synthesis that the American Chemical Society publishes an annual feature article entitled "Chiral Drugs" in its newsmagazine Chemical and Engineering News.4 ii. ' Access to Enantiomerically Pure Compounds Access to enantiopure compounds6 may be gained commonly in a number of ways. First, they may be isolated from natural sources. One must realize, however, that although it is commonly believed that many natural products can be isolated as pure enantiomers, there are a number of cases in which the isolated natural product is not enantiopure.7 For example, commercially available (+)-a-pinene (3), (-)-a-pinene (ent-3), and (-)-/?-pinene (4), all derived 4 from natural sources, are only 92%, ~81%, and 92% enantiopure, respectively.8 The enantiopurity of (fl)-(+)-citronellol (5) ranges from 35-92%,9a-b while that of (S)-(-)-citronellol (ent-5) is -75-85%. 9 c _ f More drastically, (IS, 5#)-karahana lactone (6),7a a constituent of the Japanese hop Humulus lupulus, is present in only 1.3% e.e. (K)-Dihydroactinidiolide (7),7a the (+)-a-pinene (-)-a-pinene (-)-j3-pinene (R)-(+)-citronelloI (S)-(-)-citroneilol (IS, 5/f)-karahana (3) (ent-3) (4) (5) (ent-5) lactone (6) (fl)-dihydroactinidiolide (7) (2S, 5/?)-2,5-epoxy-6,8-megastigmadiene (8) °t6 (+)-camphor (9) (+)-kaurene (10) queen recognition pheromone of the red imported fire ant Solenopsis invicta Buren, can be isolated from tobacco leaves in 30% e.e., while (2S, 5#)-2,5-epoxy-6,8-megastigmadiene (8),7a a constituent of Osmanthus fragrans Lourd, is present in 11% e.e. Thus, it is advisable that the enantiopurity of all isolated natural products be regarded with caution and where possible, checked by direct methods other than specific rotation. Furthermore, although some natural products are biosynthesized in both enantiomeric forms (e.g. camphor (9), carvone (2), a-pinene (3), and kaurene (10)) , 7 a the majority of natural products are biosynthesized in only a single enantiomeric form. If one requires the "unnatural" enantiomer of such a compound, one must resort to the chemical synthesis of that enantiomer.2b Secondly, enantiomerically pure compounds may be obtained through the resolution of a racemic mixture of compounds.63 Typically, this method involves the derivatization or complexation of the racemic compound with an enantiopure chiral auxiliary. The derivatives or complexes thus formed would be diastereomers that can be separated through conventional 5 methods such as chromatography or crystallization. An illustration of this method can be found in a report by Mosher and co-workers,10 in which they describe in detail the resolution of enantiomeric 2-phenyl-3-methylbutanoic acids by recrystallization of the diastereomeric salts formed with (i?)-(+)-(l-phenylethyl)amine. Alternatively, the enantiomers themselves can be separated by chromatography in which a chiral stationary phase is used ('chiral chromatography').11 The main disadvantages of resolution methods in general are that the maximum yield of the desired enantiomer can be no greater than 50%, and that the undesired enantiomer is often discarded. Furthermore, the resolution procedures, in practice, may be tedious due to the need for repeated recrystallization or chromatography, and if chiral chromatography is employed as the method of choice, the chiral column packing can be rather expensive. As well, if it is necessary to convert a racemic mixture into a mixture of diastereomers through derivatization with a chiral auxiliary, then at least two additional synthetic operations must be incorporated into the synthetic scheme: one step to introduce the chiral auxiliary, and another to remove it. Thus, in view of the potential difficulties associated with resolution procedures, the possibility of synthesizing only one enantiomer of an optically active compound becomes attractive. Approaches toward the synthesis of enantiopure compounds fall into two broad categories. In the first, one uses an enantiopure, often structurally simple compound as a building block for the synthesis of the desired synthetic target.6 If this building block is available in either enantiomeric form, then the possibility of synthesizing either enantiomer of the product exists, and the synthetic route is then termed 'enantiospecific' Such enantiopure starting materials, which include sugars [e.g. D-glucose ( l l ) ] , 1 2 terpenoids [e.g. carvone (2), camphor (9), and (+)-a-pinene (3)],1 2 b-1 3 a-amino acids [e.g. L-glutamic acid (12)],12b-14 and alkaloids [e.g. (-)-ephedrine (13)],1 2 b are often referred to collectively as the 'chiral pool.' Tabulations of commonly used chiral pool starting materials have been made, 6 a while other monographs and review articles illustrate how specific classes of chiral pool starting materials, 6 for example sugars123 and monoterpenoids,13 have been used for the synthesis of specific natural products. HC O H D-glucose (11) N H , H O j C ^ ^ ^ ^ C O a H L-glutamic acid (12) O H • NHMe (-)-ephedrine (13) The second major approach to synthesizing enantiopure compounds involves the conversion of a prochiral molecule to an enantiomerically enriched, or more preferably, enantiopure compound. This method is commonly known as 'asymmetric synthesis.'15 One common asymmetric synthetic strategy involves the use of enantiopure chiral auxiliaries16 that, when covalently bonded to a prochiral substrate, can bias the direction of approach of an external 16a Use of a Chiral Auxiliary Ph _ / Ph Ph. O C 0 2 H Use of a Chiral Reagent or Catalyst O H 0.54 eq. Ti(OPr')4,0.64 eq. (/?^)-(+)-diethyl tartrate 2.0 eq. r-BuOOH, C H 2 C 1 2 , -70-K) °C Use of a Biological Catalyst 0 18a . O H (96.8% e.e.) Geotrichum candidum 75% O H ^ A ^ C 0 2 E t (99% e.e.) Scheme 1.1. Examples of Common Asymmetric Synthetic Methods. reagent. After the desired chemical transformation has taken place, the chiral auxiliary can be removed to yield an enantiopure or enantiomerically enriched product. Another strategy involves the development of chiral reagents or catalysts17 that can differentiate the prochiral 7 groups or faces of the starting material. Alternatively, biological catalysts can also be used to effect the asymmetric transformation.18 The tendency for different enantiomers to react at different rates with other chiral reagents, either biological or chemical, can also be exploited in asymmetric synthesis in a procedure known as 'kinetic resolution.'19 Some representative examples of asymmetric synthetic strategies mentioned above are presented in Scheme 1.1. (b) Use of Camphor as an Enantiopure Starting Material in Natural Product Synthesis L Introduction A 'chiral pool' monoterpenoid that is commonly used as a starting material for natural product synthesis is camphor (9). Camphor (9),2 0 a known since antiquity, is a bridged bicyclic compound that occurs naturally in both enantiomeric forms as well as in racemic form. The more abundant (+)-camphor (9) can be isolated20 from Cinnamomum camphora Nees, Salvia officianalis (sage), and Santolina chamaecyparissus (lavender), among others, while (-)-camphor (+)-camphor (-)-camphor (9) (ent-9) (ent-9) can be isolated from Artemesia tridentata, Rosemarinus officianalis (rosemary), and Blumea balsamifera, among others. Camphor can be isolated in racemic form from Chrysanthemum sinense var. japonicum. In addition, camphor may be obtained through chemical synthesis.21 Moreover, both enantiomers of camphor are commercially available, and Rautenstrauch and co-workers have determined recently that the enantiopurities of samples of (+)- and (-)-camphor from these sources (e.g. Aldrich Chemical Co.) are 99.6% and 98.3%, respectively.22 The numbering system that is most commonly used when referring to camphor is shown above, and will be employed throughout this thesis. For completeness, however, in the IUPAC 8 nomenclature system, camphor is named bornan-2-one and positions C(8) and C(9) are reversed. Furthermore, in the early literature (before -1940) the C(3), C(8), C(9), and C(10) positions were designated as a, cis-n, trans-n, and co (or fS). The versatility of (+)-camphor (9) and (-)-camphor (ent-9) as enantiopure starting materials in natural product synthesis13'23 is due to the fact that the camphor structure can be functionalized regioselectively at every available position, that is, at C(3), C(4), C(5), C(6), C(8), C(9), and CQO). Furthermore, cleavage of the C(l)-C(2), C(2)-C(3), and C(l)-C(7) bonds of suitably functionalized camphor derivatives provides a variety of intermediates that have potential in organic synthesis. It must be noted that both enantiomers of camphor have also been converted to derivatives that have found widespread use as chiral auxiliaries.1615 Unfortunately, discussion of this topic is beyond the scope of this thesis. In the remainder of this chapter will be presented a brief survey of the key transformations of camphor (9) and its derivatives. A short presentation on the use of camphor (9) and its derivatives as an enantiopure starting material in natural product synthesis will also be given. C(10) Substitution: Camphor-10-sulfonic Acid (14). etc. (+)-camphor (9) .24 1 (+)-camphor-10-sulfonic acid (14) S0 2 Br iv 25 (+)-camphor-10-sulfonyl bromide (+)-10-bromo-campbor (18) (i) H 2 S 0 4 - A c 2 0 (1:2) (ii) K O H , MeOH (iii) PBr 3 (iv) xylene, heat (v) E t 3 N , C H 2 N 2 , 10-methylene-E t 2 0 ; 95°C. camphor (19) Scheme 1.2. Preparation of C( 10)-Substituted Derivatives of Camphor. Treatment of (+)-camphor (9) with sulfuric acid and acetic anhydride provides (+)-camphor-10-sulfonic acid (14; Scheme 1.2),24 which is also commercially available. The mech-9 anism (Scheme 1.3)23 proposed for this transformation is typical of many of those that have been proposed for electrophilic substitution reactions (sulfonation or bromination) or acid-catalyzed rearrangements of camphor derivatives. Protonation of (+)-camphor (9) promotes a Wagner-Meerwein rearrangement to yield the tertiary carbocation 15, which is in equilibrium with the exocyclic alkene 16. Sulfonation of 16 by sulfur trioxide, generated in situ from sulfuric acid and acetic anhydride, yields 17. A further Wagner-Meerwein rearrangement followed by deprotonation provides (+)-camphor-10-sulfonic acid (14). /JLJ 2 . W M (+)-camphor (9) 15 16 17 (+)-camphor-10-sulfonic acid (14) Scheme 1.3. Mechanism for C(10) Sulfonation of Camphor. [WM = Wagner-Meerwein rearrangement] ^ - s o r w ammonium camphor-10-sulfonate | cf. Scheme 1.2 (-)-khusimone (+)-zizanoic (-)-epi-zizanoic (-)-quadrone acid 27 acid 27 OAc 10-methylene-camphor (19) ° H OTBDMS 29 taxol intermediate Scheme 1.4. Use of C(10)-Substituted Camphor Derivatives in Natural Product Synthesis. (+)-Camphor-10-sulfonic acid (14) can also be converted to (+)-10-bromocamphor (18)25 and 10-methylenecamphor (19) 2 6 as shown in Scheme 1.2. Scheme 1.4 illustrates the use of C(10)-substituted camphor derivatives in natural product synthesis. 10 iii. C(9) Substitution: Camphor-9-sulfonic Acid (23) and 9-Bromocamphor (24) Treatment of (+)-camphor (9) with bromine in acetic acid yields (+Yendo-3-bromocamphor (20).30 When 20 is treated with fuming sulfuric acid or chlorosulfonic acid, sulfonation at C(9) occurs to yield em/0-3-bromocamphor-9-sulfonic acid (21).23 Similarly, when 20 is treated with a mixture of bromine in chlorosulfonic acid, the product that is isolated is endo-3,9-dibromocamphor (22; Scheme 1.5).31 Subsequent chemoselective reduction of the 3-bromo substituent of 21 and 22 yields camphor-9-sulfonic acid (23) and (+)-9-bromocamphor (24), respectively. It is interesting to note that direct sulfonation or bromination of (+)-camphor (9), that is, without proceeding via the 3-bromo derivative, results in the formation of an unequal mixture of enantiomeric camphor-9-sulfonic acids (23 and ent-23) or 9-bromocamphors (24 and ent-24), respectively.23 Br Br Br camphor- (+)-c/ufo-3-bromo (+)-9-dibromo-9-sulfonic acid (23) 21 camphor (20) 22 camphor (24) (i) Br 2 , HOAc, 80 °C (ii) H 2S0 4 , S03; or C1S03H (iii) Zn, HOAc-Et 20,0 °C (iv) Br 2 , CISO3H. Scheme 1.5. Preparation of C(9)-Substituted Camphor Derivatives. The proposed mechanism for C(9) sulfonation or bromination23 is given in Scheme 1.6. Protonation of endo-3-bromocamphor (20) promotes a Wagner-Meerwein rearrangement and then e;t0-3,2-methyl shift to yield 26 which is in equilibrium with the exocyclic alkene 27. Sulfonation or bromination of 27 yields tertiary carbocations 28 or 29, respectively, which 11 undergo subsequent exo-3,2-methyl shift, Wagner-Meerwein rearrangement and proton loss to yield enrfo-3-bromocamphor-9-sulfonic acid (21) or enrfo-3,9-dibromocamphor (22), respectively. S0 3 21 (X = S03H) 30 (X = SO3H) 22 (X = Br) 31 (X = Br) Scheme 1.6. Mechanism of C(9) Sulfonation or Bromination of (+)-endo-3-Bromocamphor (20) [WM = Wagner-Meerwein rearrangement; 3,2-exo-Me = 3,2-exo-methyl shift] In general, 9-bromocamphor (24) has been used more extensively in natural product synthesis than the corresponding sulfonic acid derivative 23. A selection of natural products that have been synthesized from 9-bromocamphor is presented in Scheme 1.7. 1 2 34 O steroid intermediates (+)-isoepicampherenol \ 3 (verbesenol) 32a 34 (+)-epi-/3-santalene ' (+)-9-bromo-camphor (24) (-)-furodysin30b (-)-furodysinin30b i \ (+)-a-santaloI (+)-/?-santalol OMe (+)-hapalindole Q MeO (-)-cannabidiol dimethyl ether 35 Scheme 1.7. Use of 9-Bromocamphor (24) in Natural Product Synthesis. iv. Q9.10) Disubstitution: 9.10-Dibromocamphor (33) and Intermediates Derived from the Ring-Cleavage of 9dO-Dibromocamphor (33) Prolonged treatment of (+)-e«do-3,9-dibromocamphor (22) with bromine in chlorosulfonic acid yields (+)-3,9,10-tribromocamphor (32; Scheme 1.8). The reaction mechanism for C(10) bromination in this reaction is similar to that presented previously for C(10)-sulfonation (cf. Scheme 1.3). Chemoselective removal of the 3-bromo substituent using zinc dust in 1:1 acetic acid-diethyl ether provides (+)-9,10-dibromocamphor (33).38>39 9 Br Br Br (+)-e/uf0-3-bromo- (+)-cndo-3,9-dibromo- (+)-em/o-3,9,10-tribromo- (+)-9,10-dibromo-camphor(20) camphor (22) camphor (32) camphor (33) (i) Br 2 , C1S03H, 5 h (ii) Br2, C I S O 3 H , 5-8 d (iii) Zn, 1:1 HOAc-Et 2 0,0 °C Scheme 1.8. Preparation of (+)-9,10-Dibromocamphor (33). G0 2 H Y Br (+)-9,10-dibromo-camphor (33) KOH 5:1 DMSO-H 2 0 1 h NaOMe MeOH KOH 9:1DMS0-H 2 0 90 °C (34) — I (35) KOH, A g 2 0 99:1 DMSO-H 2 0,70 °C, 1 h C0 2 Me (36) C 0 2 H (37) Scheme 1.9. Base-Promoted Ring Cleavage of (+)-9,10-Dibromocamphor (33). 39 14 The considerable utility of 9,10-dibromocamphor (33) in synthesis derives from the presence of an a,a-disubstituted-j3-bromocarbonyl unit, which promotes facile Grob fragmentation (Scheme 1.9) upon treatment with base (KOH or NaOMe) to yield bromo-acid 34, bicyclic lactone 35, bromo-ester 36, or hydroxy-acid 37. 3 9 The synthetic potential of these four derivatives 34 through 37 is illustrated in Scheme 1.10. Recent applications of (-)-9,10-dibromocamphor (eni-33) in natural product synthesis are provided also in Chapters 2 and 3 of this thesis (vide infra). O H California red scale pheromone43 Scheme 1.10. Use of (+)-9,10-Dibromocamphor (33) in Natural Product Synthesis. 15 v. C(8) Substitution: 8-Bromocamphor (38) Of the various literature routes to 8-bromocamphor (38),23 the most efficient involves the initial conversion of (+)-camphor (9) to (+)-3,3-dibromocamphor (39) using bromine (2-5 eq.) in acetic acid (Scheme 1.11). Further bromination of 39 using bromine in chlorosulfonic acid yields (+)-3,3>8-tribromocamphor (40). Chemoselective reduction of the C(3) gem-chbromo substituents with zinc dust in acetic acid affords enantiopure (+)-8-bromocamphor (38).46 Br Br (+)-camphor (9) (+)-3,3-dibromo- (+)-3,3,8-tribromo- (+)-8-bromo-camphor (39) camphor (40) camphor (38) (i) Br 2 , HOAc, 80 °C (ii) Br 2 > C1S0 3 H (iii) Zn, HOAc. Scheme 1.11. Preparation of (+)-8-Bromocamphor (38). The proposed mechanism for the bromination of 3,3-dibromocamphor (39) is outlined in Scheme 1.12.23 Protonation of 3,3-dibromocamphor (39) promotes Wagner-Meerwein rearrangement to yield the tertiary carbocation 41. At this point, a 3,2-emfo-methyl shift occurs to afford carbocation 42, which is in equilibrium with the exocyclic alkene 43. Bromination of 43 followed by successive 3,2-endo-methyl shift, Wagner-Meerwein rearrangement, and proton loss yields 3,3,8-tribromocamphor (40). It is interesting to note that there is an almost exclusive preference for 3,2-exo-methyl shifts over 3,2-endo-methyl shifts in rearrangements involving bicyclo[2.2.1]heptyl carbocation intermediates.47 Indeed it has been shown that in the absence of special structural features,48 molecules tend to rearrange by circuitous routes49 involving 3,2-exo-methyl shifts rather than simpler, more direct routes involving 3,2-ewfo-methyl shifts. However, experimental support for the proposed mechanism presented in Scheme 1.12 has been obtained through the results of comprehensive labelling studies. Investigations using 3,3-dibromo-8-deuteriocamphor (46) and 16 3,3-dibromo-9-deuteriocamphor (47) 4 6 a- 5 0 as starting materials have provided evidence that is completely consistent with the mechanism of C(8) bromination outlined in Scheme 1.12. In addition, we have isolated and characterized l,7-dibromo-4-methylcamphenilone (48) 4 6 c-d; 5 1 and l,7-dibromo-4-(bromomethyl)camphenilone (49; cf. Scheme 1.12) , 4 6 d - 5 2 which are formed as by-products in the bromination of (+)-3,3-dibromocamphor (39). Recently, Antkowiak and 51 50 Scheme 1.12. Bromination of (+)-3,3-Dibromocamphor (39): Proposed Mechanism for the Formation of (+)-3,3,8-Tribromocamphor (40) and Accompanying By-products. [WM = Wagner-Meerwein rearrangement; 5,2-endo-Me = 3,2-endo-methyl shift; 3,2-exo-Br = 3,2-txo-bromide shift.] 17 Antkowiak53 re-investigated the bromination of 3,3-dibromocamphor (39) and isolated from the reaction mixture a minor by-product which they identified as the tefrabromo-alcohol 51, presumably derived also from intermediate 50 (Scheme 1.12). D-Br 3,3-dibromo-8-deuterio-camphor (46) o l C ^ D Br 3,3-dibromo-9-deuterio-camphor (47) 52 54 54 (+)-longicamphor (+)-longiborneol (+)-longifolene 54 34 34 (+)-sativene (-)-copacamphene 1/ / (+)-«• santalene (+)-8-bromo-camphor (38) (-)-/J-santalene 34 (-)-campherenone .34 (+)-copaborneol (-)-campherenoI"' Scheme 1.13. Use of (+)-8-Bromocamphor (38) in Natural Product Synthesis. 18 Furthermore, the use of 3,3-dibromo-9-deuteriocamphor (47) as an alternative bromination substrate led to the isolation of the deuterated tetrabromo-alcohol 52 (p. 17),53 which provides additional support for the validity of the proposed mechanism as well as for the occurrence of a 3,2-endo-methyl shift during the bromination reaction. Finally, the application of 8-bromocamphor (38) to the synthesis of natural products is summarized in Scheme 1.13. vi. C(5) Substitution: 5-Bromocamphor (53). 5-Ketobornyl Acetate (59) and 5-Ketoiso-bornyl Acetate (62) Among the several methods available23 for the preparation of (+)-5-bromocamphor (53) from (+)-camphor (9; cf. Scheme 1.14), the most efficient and convenient55 involves the initial conversion of (+)-camphor (9) to (+)-3,3-dibromocamphor (39) using bromine (2-5 eq.) in acetic acid. Treatment of (+)-3,3-dibromocamphor (39) with diethylzinc in refluxing benzene yields 3.5- cyclocamphanone (54), and subsequent reaction of 54 with hydrobromic acid in acetic acid yields (+)-5-bromocamphor (53). Our research group has demonstrated recently that 5-bromocamphor (53) can be converted also to (-)-5,6-dehydrocamphor (56)56 and (-)-5-methyl-5.6- dehydrocamphor (57),57 compounds that are envisioned to have considerable potential in terpenoid synthesis (vide infra). (-)-5,6-dehydro-camphor (56) (-)-5-methyl-5,6-dehydrocamphor (57) 19 (+)-3,3-dibromocamphor (39) (+)-camphor (9) (-)-camphorquinone (55) (i) Br 2 , HOAc, reflux, 5 h (ii) Et 2 Zn, Q H ^ reflux, 24 h (iii) HBr (48%), HOAc, 65°C, 3 h (iv)- Se0 2 , A c 2 0 (v) N H 2 N H 2 , EtOH (vi) HgO, Q H s , reflux, 8 h (vii) T s N H N H 2 , HOAc (viii) NaOH, H 2 0 , pentane (ix) alumina (x) C u , ( C H 2 O H ) 2 (xi) C F 3 C F 2 C F 2 C 0 2 A g , T H F . Scheme 1.14. Preparation of (+)-5-Bromocamphor (53). One can also introduce oxygen functionality into the C(5) position of camphor (9; Scheme 1.15). Direct oxidation of (+)-bornyl acetate (58) 5 7' 5 8 with chromium(VI) oxide in acetic acid yields a mixture of 5-ketobornyl acetate (59) and 6-ketobornyl acetate (60), while similar oxidation of (-)-isobornyl acetate (61)59 yields a 4:1 mixture of 5-ketoisobornyl acetate (62) and 6-ketoisobornyl acetate (63). In a related vein, C(5) hydroxylation of (+)-bornyl acetate (58) and (-)-isobornyl acetate (61) to yield 5-hydroxybornyl acetate (64) and 5-hydroxyisobornyl acetate (65), respectively, can also be effected microbiologically.588>60 Both 5-ketobornyl acetate (59) and 5-ketoisobornyl acetate (62) have been used in natural product synthesis, as illustrated in Scheme 1.15. 20 i, ii (+)-camphor (9) iv, u ft OAc O H 5-hydroxybornyl acetate (64) f ' 2r° OAc 6-ketobornyl acetate (60) [minor] + iii OAc (+)-bornyl acetate (58) (-)-isobornyl acetate (61) l v A c O . \ ^ OH 5-hydroxyisobornyl acetate (65) 5-ketobornyl acetate (59) [major] O 5-ketoisobornyl acetate (62) SB*0 6-ketoisobornyl acetate (63) [minor] (+)-e/w'-/3-necrodoI Hartjr nojigiku 1 u i 5 9 b alcohol (i) Ca, N H 3 (ii) Ac 2 0 , C 5 H 5 N (iii) C1O3, HOAc or CrO?, A c 2 0 , HOAc (iv) UAIH4, THF, 0 °C (v) Helminthosproium sativum or Fusarium culmorum. Scheme 1.15. Preparation and Use of C(5)-Oxygenated Camphor Derivatives in Natural Product Synthesis. va. C(6) Substitution: 6-Bromocamphor (66) and 5.6-Dehvdrocamphor (56) Two alternative methods 4 6 3- 6 1 for accessing (-)-e/tcfo-6-bromocamphor (66) are presented in Scheme 1.16. Of the two routes, the relatively low-yielding, acid-catalyzed rearrangement of (+)-end<?-3-bromocamphor (20) to (-)-e/ido-6-bromocamphor (66)46a represents the most convenient method, and can also be carried out on relatively large scale (~120 g starting material) in the laboratory. 21 (66% - 85%) Br 2 , HOAc C1S0 3 H, 50°C, 15 min (36%) Br (-)-endo-6-bromo-camphor (66) Br (+)-camphor (9) (+)-c/w/o-3-bromo-camphor (20) K M n 0 4 O N a B H 4 O H Z n B r 2 Br (+)-a-pinene (3) Scheme 1.16. Preparation of (-)-e«do-6-Bromocamphor (66). The mechanism that has been proposed to explain the acid-catalyzed rearrangement of (+)-endo-3-bromocamphor (20) is shown in Scheme 1.17, and like those presented in previous sections of this thesis, is thought to involve a series of skeletal rearrangements of the camphor structure. Protonation of 20 followed by a Wagner-Meerwein rearrangement yields the tertiary carbocation 67. A 3,2-exo-methyl shift gives rise to an isomeric carbocation 68, which undergoes a further Wagner-Meerwein rearrangement to yield the secondary carbocation 69. A 6,2-hydride shift then occurs to afford the isomeric carbocation 70. Finally, a sequence comprising a Wagner-Meerwein rearrangement, 3,2-exomethyl shift, another Wagner-Meerwein rearrangement, and a final deprotonation step yields (-)-6-bromocamphor (66). Dehydrobromination of (-)-6-bromocamphor (66) yields (+)-5,6-dehydrocamphor (56)62 as well as a by-product, (-)-a-campholenic acid (73), that is derived from the cleavage of the C(l)-C(2) bond of (-)-6-bromocamphor (66; Scheme 1.18). The utility of 5,6-dehydrocamphor (56) as an intermediate in organic synthesis lies in the fact that addition of appropriate alkenyllithium or alkenyl Grignard reagents yields intermediates bearing a 1,5-diene sub-unit [cf. 74] that can undergo subsequent anionic oxy-Cope rearrangement to yield substituted hydrindenones [cf. 75] 6 2 22 H ; W M Br (+)-e/u/0-3-bromo-camphor (20) I Br (-)-endo-6-bromo-camphor (66) •OH 3,2-exo-Me + .OH W M O H 67 68 Br H 69 J 6,2-H W M ; - H ^ K . O H O - N ^ K 1 - B r , O  32-exo-Me, O H W M Br — O H Br 72 71 70 Scheme 1.17. Mechanism of the Acid-Catalyzed Rearrangement of (+)-e«do-3-Bromocamphor (20) to (-)-e«rfo-6-Bromocamphor (66) [WM = Wagner-Meerwein rearrangement; 32-exo-Me 3,2-exo-methyl shift; 6,2-H = 6,2-hydride shift]. K O H D M S O - H 2 0 , //_ 120 °C 5 O + (-)-endo-6-bromo-camphor (66) (+)-5,6-dehydro-camphor (56) M C 0 2 H (-)-a-campholenic acid (73) Ri [M = MgBr, Li] R? anionic oxy-Cope rearrangement R 74 75 Scheme 1.18. Preparation and Synthetic Potential of (+)-5,6-Dehydrocamphor (56). 23 The use of (+)-5,6-dehydrocamphor (56) in natural product synthesis is currently being evaluated in our laboratory. In a projected formal, enantiospecific synthesis63 of the marine sesquiterpenoids furodysin (76) and furodysinin (77; Scheme 1.19), addition of isopropenylmagnesium bromide to (+)-5,6-dehydrocamphor (56) yields an alkoxy-l,5-diene intermediate that is not isolated but subjected to anionic oxy-Cope rearrangement to yield the diastereomeric hydrindenones 78. Ozonolysis of 78 followed by intramolecular acid-catalyzed aldol condensation provided bicyclic keto-enones 79. Chemoselective protection of the saturated (i) H2C=C(CH3)MgBr, THF, 20 °C, 1.5 h; reflux, 5 h (ii) 03,1:1 CH 2 Cl 2 -MeOH; Zn, HOAc; p-TsOH, C 6H6, reflux (iii) (CH 2OH) 2 , p-TsOH, C6H6, reflux (iv) L i , N H 3 , EtOH, THF (v) NaH, THF; CH 3 I ( v i ) l M H C l , acetone (vii) HN(SiMe3)2, Me 3SiCl, L i l , CH 2C1 2,0 °C; PhSeCl, Et 2 0, -78-*0 °C; HOAc, H 2 0 2 , 0 °C-w.t. Scheme 1.19. Money and Wong: Formal Synthetic Approach to (-)-Furodysin and (-)-Furodysinin.* ketone functional group in 79 yielded the corresponding ketal-enones 80, and subsequent lithium-liquid ammonia reduction of 80 gave the diastereomeric ketal-alcohols 81. Protection of 24 the ketal-alcohols 81 as the corresponding methyl ethers 82 and ketal hydrolysis yielded the bicyclic ketones 83, which were converted to the a,/£-unsaturated ketones 84 (HN(SiMe3)2, Me3SiI, Et20; PhSeCl; H2O2, HOAc). It is envisioned that deoxygenation at C(7) and functional group interconversion at C(4) should provide keto-alkene 85 which has already been converted to (±)-furodysin (76) and (±)-furodysinin (77) by Hirota and co-workers.64 Other applications of 5,6-dehydrocamphor (56) and 5-methyl-5,6-dehydrocamphor (57) to terpenoid synthesis are illustrated in Scheme 1.20.57-65 (-)-5-methyl-5,6-debydrocamphor (57) Scheme 1.20. Use of (+)-5,6-Dehydrocamphor (56) and (-)-5-Methyl-5,6-dehydrocamphor (57) in the Synthesis of Terpenoid Intermediates. viii. C(3) Substitution: Camphorquinone (55) The trivial conversions of (+)-camphor (9) to (+)-eAido-3-bromocamphor (20) [Br2 (1.1 eq.), HOAc, 80 °C] and (+)-3,3-dibromocamphor (39) [Br2 (2-5 eq.), HOAc, 80 °C] have already been presented in Schemes 1.5 and 1.11, respectively, and will not be discussed further in this section. However, when (+)-camphor (9) is treated with excess selenium(IV) oxide in 25 refluxing acetic anhydride,66 a tandem ene reaction-[2,3] sigmatropic rearrangement occurs to yield (-)-camphorquinone (55), a crystalline, bright yellow solid. The use of camphorquinone (55) in natural product synthesis is summarized in Scheme 1.21. Of note, the enantiospecific total synthesis of taxol (86) by Holton and co-workers71 employed /3-patchoulene oxide (87),69 derived from (+)-camphorquinone (ent-55) and originally from (-)-camphor (ent-9), as the starting material. Scheme 1.21. Use of (+)- and (-)-Camphorquinone in Natural Product Synthesis. 26 ix. C(4) Substitution: 4-Methvlcamphor (87) Several research groups have reported synthetic routes to 4-methylcamphor (87). 2 3 a However, in none of these reports was the enantiopurity of the final product ascertained. Our studies on the acid-catalyzed rearrangement of 2-methylenebornane (88) [H2SO4, HOAc] culminated in a new synthesis72 of (-)-4-methylcamphor (87) from enantiopure (+)-camphor (9; Scheme 1.22, top). As part of the same project, the enantiopurity of the synthesized (-)-4-methylcamphor (87) was determined by a NMR method employing a chiral lanthanide shift reagent. Although the specific rotation of our sample of 87 compared favorably with those quoted in the literature, the results of our NMR study suggested that our sample of (-)-4-methylcamphor (87), as well as those obtained through the alternative literature methods, was only 60% enantiopure! However, recent work in our laboratory has resulted in the development (+)-camphor (-)-2-methylene (+)-4-methylisobornyl (+)-4-methyl- (-)-4-methyl-(9) bornane(88) acetate (89) isoborneol (90) camphor (87) I [60% e.e.] 4-methylisobornyl 92 (endo-2-hydroxy) (-)-4-methyl-bromide (91) 90 (exo-2-hydroxy) camphor (87) [-100% e.e.] (i) C H 3 P P h 3 + B f , BuLi, THF, reflux (ii) H 2 S 0 4 , HOAc (iii) L i A l H 4 , T H F , 0 °C; H 2 0 (iv) C r 0 3 , aq. H 2 S 0 4 > acetone, 0 °C (v) HBr, HOAc (vi) Mg, THF, 0 °C; 0 2 ; H 3 0 + . Scheme 1.22. Preparation of (-)-4-Methylcamphor (87) from (+)-Camphor.72,73 of an improved route73 that yields enantiopure (-)-4-methylcamphor (87; Scheme 1.22, bottom). A more detailed discussion of the enantiopurity and substitution chemistry of 4-methylcamphor (87) will be presented in Chapter 4 of this thesis. 27 x. Cleavage of the C(2 )-C(3) Bond of Camphor Oxidative cleavage of the C(2)-C(3) bond of (+)-camphor with nitric acid in the presence of mercury(II) sulfate74 results in the formation of the monocyclic (+)-camphoric acid (93; Scheme 1.23). In addition, both enantiomers of camphoric acid (93) are commercially available, and Meinwald's recent synthesis of a-necrodol, /3-necrodol, epi-a-necrodol, and epj-/3-necrodol (Scheme 1.23)75 serves to exemplify the use of camphoric acid (93) in natural product synthesis. (+)-ep/-a-necrodol (+)-e/?i-/?-necrodol Scheme 1.23. Cleavage of the C(2)-C(3) Bond of Camphor; Use of Camphoric Acid (93) in Natural Product Synthesis. In 1902, the British chemists Armstrong and Lowry remarked,76 "No substance known to us suffers rearrangement of its parts and undergoes a complete change of type more readily than does camphor..." Now, in 1996, in view of what is known about the transformations of camphor, the modern chemist can still find reason to agree with Armstrong and Lowry. The preceding discussion was intended both as a cursory introduction to the fascinating chemistry of camphor and an exhibition of the variety of natural products into which the camphor structure has been successfully transformed. The interested reader can find more detailed and specialized treatments of these topics in recent reviews or monographs.13'23 In the following chapters are described the results of some of our most recent investigations on the use of (-)-camphor (ent-9) as an enantiopure starting material in pseudoguaianolide (Chapter 2) and limonoid (Chapter 3) synthesis, and on aspects of the unusual chemistry of 4-methylcamphor (87) and its derivatives (Chapter 4). 28 Chapter 2 A Formal, Enantiospecific Synthesis of Pseudoguaianolides 29 120 2. A Formal, Enantiospecific Synthesis of Pseudoguaianolides (a) Introduction The pseudoguaianolides77 are a relatively large group of tricyclic sesquiterpenoid lactones that have been isolated from plants of the Compositae family, which are found generally in the southern United States and Central America. The basic pseudoguaiane skeleton and num-bering system is given in structure 94. A common structural feature in many pseudoguaianolides (cf. Scheme 2.1) is a trans-fused bicyclic 5/7-ring system to which is fused a third ring that forms an a-methylene-y-lactone unit. This family of compounds is further divided into two categories on the basis of the orientation of the C(10)-methyl group. Compounds (cf. Scheme 2.1) in which the C(10)-methyl group adopts an a-orientation are classified as helenanolides Helenanolides H \ ' H\ H \ H \ 3 < A 13 12 94 95: helenalin 96: carpesiolin 97: bigelovin 98: mexicanin I (R=H) 99: linifolin A (R=OAc) Ambrosanolides o 100: ambrosin (R = H) 101: parthenin (R = OH) 102: confertin O 103: damsin O 104: neoambrosin Scheme 2.1. Structures of Representative Pseudoguaianolides 30 (after helenalin (95)) while compounds (cf. Scheme 2.1) in which the same methyl group adopts a /3-orientation are classified as ambrosanolides (after ambrosin (100)). (b) Previous Synthetic Routes to Pseudoguaianolides Much work has been done to investigate the biological activity of members of the pseudoguaianolide family. 7 8 The cytotoxicity and anti-neoplastic activity of helenalin (95), for example, is attributed to the presence of the a-methylene-y-lactone and ring A a,/3-unsaturated cyclopentenone moieties in the molecule.78 It has been discovered, generally, that many pseudoguaianolides display anti-inflammatory, cytotoxic, anti-leukemic, anti-tumor, anti-bacterial, dermatological, or insect antifeedant properties.78 Consequently, much attention has been directed towards the total or partial synthesis of these compounds. 7 9 - 8 8 Present space limitations do not permit a comprehensive examination of the synthetic work done on this class of compounds. Fortunately, much of this work has already been reviewed.7 9 Thus, for illustrative purposes, only a small subset of these syntheses will be highlighted. In 1979, Roberts and Schlessinger reported a synthesis of (±)-helenalin (95)81 from bicyclic enone 105 (Scheme 2.2). Bicyclic enone 105 was converted to the lactam 106 via a Beckman rearrangement reaction. Ring contraction of lactam 106 gave hydroxy-aldehyde 107. Subsequent treatment of 107 with base promoted a retro-aldol/aldol reaction sequence that provided the hydrazulenone 108. Conjugate addition of methylmagnesium bromide to enone 108 occurred from the face of the enone opposite the C(5) methyl group to afford ketone 109. At this point the newly introduced stereocenter at C(10) had the correct (10/?) configuration required for the synthesis of helenalin. Standard functional group manipulations were used to convert ketone 109 to dienone 110. Addition of dilithioacetate to epoxide 111, derived from 110, followed by lactonization, or-methylenation, and oxidation completed the synthesis of (±)-helenalin (95). The above synthesis of (±)-helenalin (95) served also to lay the foundation for syntheses of the ambrosanolides (±)-confertin (102) and (±)-damsin (103) by Quallich and Schlessinger.82 31 helenalin (95) 111 110 109 (a) CH3NHOH .HCI, C 5 H 5 N , 40 °C (b) p-TsCl, C 5 H 5 N (c) LiCH 2PO(OMe)2, T H F , -78 °C (d) NaOAc, HOAc, H 2 O , E t 2 O , 0 ° C (e) f-BuOH, r-BuOK (0 CH 3 MgBr, Cul, Me 2 S, E t 2 0 , 0 °C (g) HC1, MeOH, 0 °C (h) ( C H 2 O H ) 2 , p-TsOH, C 6 H6,90 °C (i) PCC, NaOAc, C H 2 C 1 2 (j) NaH, PhSSPh, D M E , 45 °C;m-CPBA, C H 2 C 1 2 , 0 °C; P(OMe) 3 , P h C H 3 , 110 °C (k) DIBAL, P h C H 3 , -40 °C (1) HC1, MeOH, 0 °C (m) DHP,/?-TsOH, C H 2 C 1 2 , 0 °C (n) L i H M D S , Me 3 SiCl , THF, -78 °C (0) Pd(OAc) 2, C H 3 C N (p) NaOH, H 2 0 2 , MeOH, 40 °C (q) i -Bu 3 Al , P h C H 3 , 0 °C (r) LiCH 2 CQ2Li , THF, HMPA, 50 °C; 6 N HC1 (s) Me 3 SiCl , E t 3 N, T H F ( t ) magnesium methoxycarbonate, 140 °C (u) 30% C H 2 0 , E t 2 N H (v) M n 0 2 , CHC1 3 ,45 °C Scheme 2.2. Roberts and Schlessinger: Total Synthesis of (±)-Helenalin (95).81 Hydrazulenone 108, which had been converted to (±)-helenalin (95) as described above, served as the starting point in the confertin synthesis (Scheme 2.3). Conjugate addition of lithium dimethylcuprate to 108 followed by a Saegusa reaction yielded enone 112. Hydrogenation of enone 112 over a rhodium catalyst resulted in delivery of the elements of dihydrogen from the face of the enone opposite the C(5) methyl group to give ketone 113 with the correct (105) ambrosanolide configuration. Alkylation of 113 with f-butyl iodoacetate, followed by installation of the a-methylene-y-lactone unit yielded (±)-confertin (102). On the other hand, conversion of 113 to (±)-damsin (103) (Scheme 2.3)82 required a 1,3-ketone transposition sequence. To this end, ketone 113 was converted to enone 115 via a Saegusa reaction and then to epoxy-ketone 116. Application of the Wharton rearrangement afforded the allylic alcohol 117. After transformation of 117 to ketone 118 through standard means, the remainder of the damsin synthesis was carried out in a manner analogous to that of the synthesis of (±)-confertin (102) described above (Scheme 2.3).82 32 : 0 /-BuO ;-BuO |-108(R = H) d—h Me3SiO O :0 confertin (102) f-BuO 115 116 117 118 damsin(103) (a) M e 2 C u L i , THF, 0 °C; Me 3 SiCl, E t 3 N (b) Pd(OAc) 2, C H 3 C N (c) H 2 , R h - A l 2 0 3 , E tOH (d) L i H M D S , f -Bu0 2 C-CH 2 I , T M E D A , THF, -78 °C (e) A c 2 0 , HC10 4 > EtOAc, 0 °C (f) H 2 , R h - A l 2 0 3 , EtOH, 500 psi (g) K O H , MeOH, H 2 0 (h) Me 3 SiCl , C 5 H 5 N (i) magnesium methoxycarbonate, 140 °C (j) 30% C H 2 0 , E t 2 N H (k) Jones oxidation (1) L iHMDS, THF; Me 3 SiCl , E t 3 N , -78 °C (m) Pd(OAc) 2, C H 3 C N (n) NaOH, H 2 0 2 , MeOH, H 2 0 (o) N 2 H4, HOAc, MeOH, E t 2 0 ,0 °C (p) H 2 , R h - A l 2 0 3 , E t 2 0 (q) Jones oxidation (r) A c 2 0 , NaOAc, 140 °C. Scheme 2.3. Quallich and Schlessinger: Total Synthesis of (±)-Confertin and (±)-Damsin. 8 2 Heathcock and co-workers have completed a formal synthesis of (±)-helenalin (95; Scheme 2.4)8 3 in which the Wieland-Miescher ketone (119) was used as the starting material. The synthetic route features a pinacol-pinacolone type rearrangement of a bicyclo[4.4.0]decanol 120 to a bicyclo[4.3.0]decanone 121 en route to the relay compound hydroxy-ketone 123. The t-butyl ether of 123 had been converted previously to (±)-helenalin (95) by Roberts and Schlessinger,81 as already oudined (Scheme 2.2). T S ° O H < r \ . LQ/ L i O H Wieland-Miescher ketone (119) (±)-confertin -» (102) Me,SiO Scheme 2.4. Heathcock et al.: Formal Synthesis of (+)-Helenalin; Total Synthesis of (±)-Confertin. 8 3 33 Hydroxy-enone 122 was employed by Heathcock and co-workers also as an entry point into a total synthesis of (±)-confertin (102) (Scheme 2.4).83 Derivatization of hydroxy-enone 122, followed by alkylation with methyl bromoacetate allowed for the subsequent introduction of the a-methylene-y-lactone unit of confertin (102). Welch and Bryson employed a boron-mediated annulation reaction as the key step in their synthesis of (±)-confertin (102) and (±)-helenalin (95) (Scheme 2.5).84 Conversion of 2-methyl-2-cyclopenten-l-one (125) to the silyloxy-diene 126 followed by boron-mediated annulation with thexylborane and desilylation yielded an 30:70 epimeric mixture of ketones 123 and 128, respectively. The major epimer 128 was a relay compound in a formal synthesis of (±)-confertin (102) while the minor epimer 123 was a relay compound for the synthesis of (±)-helenalin (95). It was found that the stereoselectivity of the annulation reaction could be reversed if bromoborane were used in place of thexylborane. Under the bromoborane conditions the synthesis yielded a 77:23 mixture of the epimeric hydroxy-ketones 123 and 128, respectively. 125 126 127 (±)-helenalin (95) (±)-confertin (102) (a) H 2 C=C(CH 3 )MgBr, Cul, T H F ; PhSeCH 2 CHO (b) MsCl, E t 3 N, C H 2 C 1 2 (c) K B u 3 B H , T H F ; NaOH, H 2 0 2 (d) TBDMS-C1, /-Pr 2NEt, D M F (e) T h x - B H 2 , T H F (123/128 = 30:70) or B r B H 2 , T H F ; (123/128 = 77:23) (f) NaCN; T f 2 0 ; NaOH, H 2 0 2 (g) HF, C H 3 C N ; separation of epimers. Scheme 2.5. Welch and Bryson: Formal Synthesis of (±)-Helenalin and (l)-Confertin.84 Quinkert and co-workers have published an enantioselective synthesis of (+)-confertin85 (102) (Scheme 2.6) starting from 2-methyl-2-cyclopenten-l-one (125). Treatment of 125 with the organocuprate reagent derived from copper(I) thiocyanate, isopropenyllithium (2 eq.) and (5)-2-(ethoxymethyl)pyrrolidine resulted in the enantioselective conjugate addition of an isopropenyl group to 125 to afford an epimeric mixture of ketones 129 (88% e.e.). Ketones 129 were converted in several steps to a mixture of bicyclic silyloxy-enones 130 and 131, and 34 ultimately to silyloxy-ketone 132. Because the t-butyl analogue (113) of silyloxy-ketone 132 had been converted previously to confertin (102; cf. Scheme 2.3),82 the route by Quinkert and co-workers85 constitutes a formal synthesis of (+)-confertin (102). ° 1 2 5 M g B r . C u S C N (S)-2-(ethoxymethyl)-pyrrolidine ^ T B D M S O 1 3 Q (+)-confertin (102) H O + T B D M S O 131 H O O J T B D M S O 1 3 2 D C Scheme 2.6. Quinkert et al:. Formal, Enantioselective Synthesis of (+)-Confertin. A further synthesis of (±)-confertin (102) is that reported by Kennedy and McKervey (Scheme 2 .7). 8 6 The key step in this synthesis is a rhodium-mediated cyclization of the a-diazoketone 134, derived from the dihydrocinnamic acid derivative 133. The resulting acetoxy-ketone 135 was transformed into the bicyclic r-butyldimethylsilyloxy-ketone 132 using conventional methods. r-Butyldimethylsilyloxy-ketone 132 had already been converted into confertin (102) by Quinkert and co-workers (cf. Scheme 2.6);8 5 thus, the route reported by Kennedy and McKervey constitutes a formal synthesis of (±)-confertin (102).86 Vandewalle and co-workers carried out the photocycloaddition of 2-methyl-2-cyclopenten-l-one (125) to l,2-bis(trimethylsilyloxy)cyclopent-l-ene (136) as the initial step in their synthesis of the helenanolide (±)-carpesiolin (96; Scheme 2.8).87 Subsequent desilylation, diol cleavage, and protection of the A-ring hydroxyl group as a tetrahydropyranyl ether provided 35 the bicyclic diketone 138. Regioselective methylenation of 138, followed by tetrahydropyranyl ether hydrolysis and catalytic hydrogenation yielded the hydroxy-ketone 139 in which the desired (10/?) ambrosanolide stereochemistry was now present. Conversion of 139 to ketal-enone 140 followed by installation of the a-methylene-ylactone unit completed the synthesis of (±)-carpesiolin (96).87 36 OTHP 151 mexicanin I (98) linifolin A (99) (a) L D A , T H F , 0 °C; CH 31,0—20 °C (b) NaOH, H 2 0 2 , 1 :1 M e O H - H A 0 °C (c) NaH, T H F , H M P A ; PhCH 2 Br, B114NI (d) p-TsOH, MeOH, 0 °C (e) K O H , EtOH; H 3 0 + (0 p-TsCl, D B U , P h C H 3 , reflux (g) DIBAL, P h C H 3 , -78 °C (h) M e O C H 2 P P h 3 + C f , /-AmONa, C 6 H6 (i) 1 N HC1 (j) C H 3 L i , E t 2 0 , -20—>0 °C (k) PCC, NaOAc, C H 2 C 1 2 (1) 5% K O H , MeOH; p-TsOH, C^Ls< reflux (m) UAIH4, THF, 0 °C (n) m-CPBA, C H 2 C 1 2 (o) L i C H 2 C 0 2 L i , D M E , 43—>55 °C; L i , N H 3 (p) DHP,/>-TsOH, C H 2 C 1 2 , 0 °C—>r.L (q) L D A , T H F , -78 °C; C H 2 0 , - 2 5 ° C ( r ) M s C l , C 5 H 5 N , 0 ° C (s)DBU,C6H6 (t) H 2 0 , HOAc (2:3) (u) M n 0 2 , C H ^ - Q H e (v) A c 2 0 , D M A P , C5H5N (w) L iCH 2 C02Li , D M E , 43—>55 °C (x) Jones reagent (y) NaBHLt, EtOH, 0 °C (z) K O H , D M E ; L i , N H 3 ; NH4CI (aa) D C C , CH 2 C1 2 . Scheme 2.9. Grieco et al.: Total Synthesis of (±)-J3igelovin, (±)-Mexicanin I, and (±)-Linifolin A . 8 8 37 The synthesis of the helenanolides (±)-bigelovin (97), (±)-mexicanin I (98), and (+)-linifolin A (99) by Grieco and co-workers is summarized in Scheme 2.9. Norbornadiene (141) was converted in four steps to the bromo-keto-acid 142 and in a further seven steps to the bicyclic ketone 143. Subsequent alkylation of 143 with methyl iodide followed by Baeyer-Villiger oxidation and esterification yielded hydroxy-ester 144. Hydroxy-ester 144 was transformed presumably into benzyloxy-lactone 145 but as a result of the lactonization reaction conditions, further epimerization of the C(10) methyl group (pseudoguaianolide numbering) in 145 occurred to yield the diastereomeric benzyloxy-lactone 146 in which the correct (105) configuration required for helenanolide synthesis is present. Subsequent elaboration of 146 to the keto-aldehyde 147 permitted the aldol ring closure of 147 to provide the bicyclic enone 148. It is relevant to note at this point that the tetrahydropyranyl ether analogue of 148 was an intermediate in Roberts and Schlessinger's synthesis of (±)-helenalin (95; cf. Scheme 2.2).81 Enone 148 was converted to the epoxy-alcohol 149. Addition of dilithioacetate followed by lactonization yielded the tricyclic hydroxy-lactone 150 which was converted to (±)-bigelovin (97) via a route similar to those presented above (cf. Schemes 2.2 and 2.3). On the other hand, epimerization of the C(6)-hydroxyl group in 150 via an oxidation-reduction sequence, followed by introduction of the exocyclic methylene group and functional group manipulations made possible the synthesis of the helenanolides (±)-mexicanin I (98) and (±)-linifolin (99) by a method (Scheme 2.9) similar to that followed above for the bigelovin (97) synthesis.88 An examination of the synthetic schemes presented above reveals that all the syntheses except for Quinkert's synthesis of (+)-confertin (102; Scheme 2.6)85 yield racemic products. In fact, the recent report of the enantiospecific synthesis of (-)-neoambrosin (104), (-)-parthenin (103), and (+)-dihydroisoparthenin by Asaoka and co-workers80t represents only the second enantioselective or enantiospecific synthesis of pseudoguaianolides. The paucity of synthetic routes to enantiopure pseudoguaianolides prompted our research group to devise a new enantiospecific route (Scheme 2.10) to the enf-helenanolides from (+)-camphor (9). Previously, we have demonstrated that (+)-9,10-dibromocamphor (33),38 derived from (+)-camphor (9; cf. 38 Scheme 1.8), can undergo facile ring cleavage to yield a variety of cyclopentanoid derivatives, including the bicyclic lactone 35 (cf. Scheme 1.9).39 In noting the structural similarity between lactone 35 and the A ring of the pseudoguaianolides, and that the relative configurations of the two stereocenters in lactone 35 are the same as those present at C(l) and C(5) of most pseudoguaianolides, we considered lactone 35 to be a potential intermediate in our projected synthesis of the m-helenanolides (cf. Scheme 2.10).42 In the event, alkylation of lactone 35 with methyl iodide occurred stereoselectively from the face opposite the C(5) methyl group to yield lactone 152. Transesterification of lactone 152 with methanol, followed by protection of the primary alcohol group as the corresponding t-butyldimethylsilyl ether and reduction of the methyl ester group yielded alcohol 153. Conversion of alcohol 153 to the corresponding iodide followed by alkylation with 2-lithio-2-methyl-l,3-dithiane yielded the dithiane derivative 154. Hydrolysis of the thioketal group in 154 yielded silyloxy-ketone 155. Subsequent hydrolysis of the silyl protective group and oxidation of the resulting primary alcohol group afforded keto-aldehyde 156, and intramolecular aldol condensation yielded the bicyclic dienone 157. 157 156 155 154 (a) Br 2 , HOAc, 80 °C (b) Br 2 , C1S0 3 H, 5 h (c) Br 2 , CISO3H, 5-8 d (d) Zn, 1:1 H O A c - E t 2 0 , 0 °C (e) K O H , 5:1 D M S O - H 2 0 , 1 h (f) K O H , Ag 20,99:1 D M S O - H 2 0 , 7 0 °C, 1 h (g) L D A , T H F , -78 °C; C H 3 I , -78 °C -»r.t . (h) M e O H , cone. H 2 S 0 4 (i) TBDMS-C1, D M A P , C H 2 C 1 2 (j) L1AIH4, T H F , 0 °C (k) MsCl , E t 3 N , C H 2 C 1 2 ( l )NaI,HMPA (rn)2-Uthio-2-methyl-l,3-dithiane,THF (n) C H 3 I , C a C 0 3 , C H 3 C N - H 2 0 , 8 0 °C (o) T B A F , T H F (p) PDC, C H 2 C 1 2 (q) K O H , MeOH (r) MsCl, E t 3 N, D M A P , C H 2 C 1 2 ; D B U . Scheme 2.10. Money et al:. An Enantiospecific Synthetic Approach to the Helenanolides.4 39 Examination of the pseudoguaianolide structures in Scheme 2.1 reveals that all examples bear a carbonyl group at C(4). In retrospect, the utility of dienone 157 in pseudoguaianolide synthesis is limited because it is difficult to introduce oxygen functionality at C(4) selectively. For example, ozonolysis of 157 would lead to oxidative cleavage of not only the exocyclic methylene group at C(4), but also the C(6)-C(7) double bond. Consequently, we revised our synthetic strategy by proposing an alternate route that could provide access to not only the helenanolides, but also the ambrosanolides. Instead of employing lactone 35 as an intermediate in our revised route, we chose to exploit the synthetic potential of hydroxy-acid ent-37?9 derived from (-)-9,10-dibromocamphor (ent-33) and in turn, from (-)-camphor (ent-9). We envisioned that by converting hydroxy-acid ent-31 subsequently to ketal-enone 140, hydroxy-enone 158, hydroxy-ketone 123 and hydroxy-ketone 128, a formal, enantiospecific synthesis of the helenanolides (+)-carpesiolin (96),87 (-)-helenalin (95),81'83 (+)-bigelovin (97),88 (+)-mexicanin I (98),88 and (+)-linifolin A (99),88 and the ambrosanolides (-f)-confertin (102)82 and (-)-damsin (103)82 would be achieved. Our results in this area are summarized in the following section. (-).helenalin (95) (+)-bigelovin (97) (+)-mexicanin I (98) (+)-carpesiolin (96) (+)-IinifoIin A (99) (-)-damsin (103) (+)-confertin (102) Scheme 2.11. Proposed Formal, Enantiospecific Syntheses of Helenanolides and Ambrosanolides Using Camphor as an Enantiopure Starting Material. 40 (c) An Enantiospecific Synthesis of Helenanolides Structural considerations (cf. Scheme 2.10) suggested that we choose (-)-carnphor (ent-9) as our starting material. Although (-)-camphor (ent-9) is commercially available, it is about five times more expensive than (-f)-camphor (9). For this reason we prefer to prepare (-)-camphor (ent-9) from the less expensive, commercially available (-)-borneol (159) instead (cf Scheme 2.12). Thus, (-)-borneol (159) was oxidized using Jones reagent (CrC>3, aqueous H 2 S O 4 , acetone) at 0 °C to provide (-)-camphor (ent-9) in excellent yield (>95%).89 160 ent-ll ent-33 ent-31 (a) C r 0 3 , aq. H 2 S 0 4 , acetone, 0 °C [97%] (b) Br 2 , HOAc, 80 °C [71%] (c) Br 2 , C I S O 3 H , 5 h [65%] (d) Br 2 , C I S O 3 H , 5-8 d (e) Zn, 1:1 E t 2 0 - H O A c , 0 °C [65% from ent-12] (f) K O H , 9:1 D M S O - H 2 0 , 9 0 °C [90%] (g) K 2 C Q 3 , D M F ; C H 3 I [95%]. Scheme 2.12. Conversion of (-)-Borneol to (-)-Hydroxy-ester 160. 3 8 , 3 y Treatment of (-)-camphor (ent-9) with one equivalent of bromine in glacial acetic acid at 80 °C afforded (-)-en<io-3-bromocamphor (ent-20) in 82% yield. Subsequent reaction of ent-20 with bromine in chlorosulfonic acid for 5 h yielded (-)-e«do-3,9-dibromocamphor (ent-22), which was purified by recrystallization from 1:1 methanol-dichloromethane. The purified dibromocamphor ent-22 was converted to (-)-ertdo-3,9,10-tribromocamphor (ent-32) through further reaction with bromine in chlorosulfonic acid for five to eight days. Chemoselective debromination of ent-32 with zinc powder in 1:1 HOAc-Et20 gave (-)-9,10-dibromocamphor (ent-33). Base-promoted ring cleavage of ent-33 (KOH, 9:1 D M S O - H 2 O ) yielded the cyclopentanoid hydroxy-acid ew/-37,38-39 and subsequent esterification ( K 2 C O 3 , DMF; C H 3 I ) 41 yielded (-)-hydroxy-ester 160. 3 9 The spectroscopic properties of hydroxy-ester 160 were identical with those reported previously in the literature.39,45 Originally it was planned at this point to convert 160 to the hydroxy-ester 161a (cf. Scheme 2.13). Protection of the C(4) hydroxyl group of 161a as the corresponding f-butyl ether would then provide a potentially useful intermediate for pseudoguaianolide synthesis. With this goal in mind, the hydroxy-ester 160 was converted to the corresponding r-butyldimethylsilyl90 ether 162a using r-butyldimethylsilyl chloride and imidazole in dry D M F . Subsequent ozonolytic cleavage (O3,1:1 CH2CI2-CH3OH, -78 °C; Me 2S) of the exocyclic methylene group in 162a yielded keto-ester 163a. H H Hi.. Me 160 OR 162a (R = TBDMS) 162b (R = TBDPS) H / ^ 4 ^ C 0 2 M e V h 0 OR 163a (R = TBDMS) 163b (R = TBDPS) H / — p ^ C 0 2 M e r h H 0 O T B D M S H X H ^ C 0 2 M e oVr""i k / ° OR 164a (R = TBDMS) 164b (R = TBDPS) H / ^ 4 ^ C 0 2 M e . . r n H 0 O T B D M S 161a 161b (a) TBDMS-C1 or TBDPS-C1, imidazole, D M F [>95%] (b) 0 3 ,1:1 C H 2 C l 2 - M e O H , -78 °C; Me 2 S, -78 °C -> r.t. [92%] (c) ( C H 2 O H ) 2 , p-TsOH, C^, reflux [92%] (d) N a B H 4 , M e O H or LiAl(OBu') 3 H, T H F (e) O3,1:1 C H 2 C l 2 - M e O H , -78 °C; NaBH4, -78 °C - » r.t. Scheme 2.13. Conversion of (-)-Hydroxy-ester 160 to (-)-Ketal-ester 164b. We then explored the possibility of carrying out a chemo- and stereoselective reduction91 of the keto group of 163a (cf. p. 224). However, treatment of keto-ester 163a with sodium borohydride in methanol at 0 °C yielded a 3:1 mixture of diastereomeric alcohols 161a and 161b, respectively. When the same reaction was conducted at a lower temperature, no significant improvement in stereoselectivity was observed. Moreover, the reaction rate was greatly reduced at lower temperatures. A procedure involving the use of a more bulky reducing agent, lithium tri(r-butoxy)aluminum hydride, 9 1 3 did not offer any significant improvement to the 42 stereoselectivity of the reduction. The direct conversion of alkene 162a to hydroxy-esters 161a and 161b (4:1; cf. Scheme 2.13 and p. 222)91b<c was likewise unattractive. The low stereoselectivity encountered at such an early stage of the synthesis, coupled with the fact that the diastereomeric alcohols 161a and 161b could be separated only after much difficulty prompted us to postpone the reduction step to a later stage of the synthesis. After revising our synthetic plan in the light of the above results, we chose to convert the keto-ester 163a (Scheme 2.13) to the corresponding ketal-ester 164a instead. Disappointingly, attempts to effect ketal formation [(HOCH2CH2OH, p-TsOH, benzene, reflux), 9 2 3 ( H O C H 2 C H 2 O H , PPTS, benzene, reflux) 9 2 b» c or (HOCH 2 CH 2 OH, Me3SiCl)92d] resulted only in cleavage of the silyl protective group or recovery of starting material 163a. Moreover, with the p-TsOH conditions, prolonged reaction times led to transesterification of the methyl ester group with ethylene glycol. The apparent lability of the silyl protective group of keto-ester 163a prompted us to consider the more robust r-butyldiphenylsilyl group9 3 as an alternative hydroxyl protective group. Thus, hydroxy-ester 160 was convened to the corresponding TBDPS ether 162b with t-butyldiphenylsilyl chloride and imidazole in DMF. Ozonolysis of 162b followed by reductive work-up with dimethyl sulfide yielded the keto-ester 163b. Conversion of the keto-ester 163b to ketal-ester 164b occurred readily, in 92% yield, upon treatment with excess ethylene glycol, p-toluenesulfonic acid in refluxing benzene.923 The identity of ketal-ester 164b was confirmed by its spectroscopic characteristics. Noteworthy in the infrared spectrum is the presence of a sharp, strong absorption at 1739 c m - 1 that can be assigned to the stretching of the ester carbonyl group in 164b. Furthermore, two weak bands at 3072 and 3055 cm - 1 , representing aromatic C - H stretches, as well as a weak band at 1589 c m - 1 , representing an aromatic C=C stretch, support the presence of a TBDPS protective group in 164b. In the 400 MHz lH NMR spectrum a multiplet at 3.72-3.84 ppm, representing protons in the - O C H 7 C H 7 O - unit, provides evidence that the desired ethylene ketal protective group has 43 been introduced successfully into the molecule. The integrity of the silyl protective group is apparent from the signals at 7.67-7.76 (m, 4H), 7.32-7.46 (m, 6H), and 1.06 (s, 9H) ppm. Furthermore, the three-proton singlet at 3.62 ppm can be assigned to the protons of the methoxycarbonyl (-CO?Me-) moiety. These data support the fact that the product obtained through this step of the synthetic sequence is in fact the desired ketal-ester 164b. Furthermore, 1 3 C NMR, APT, COSY (cf. Table 5.2, p. 130), HETCOR {cf. Table 5.3, p. 131) and mass spectral data are also consistent with those expected for 164b. ( a ) L D A , T H F , - 7 8 ° C ; C H 3 I , - 7 8 ° C — > r . t . [95%] (b) L1AIH4, THF, 0°C [96%] (c) I2, PPh 3 , imidazole, E t 2 0 - C H 3 C N (5:3) [85%] (d) 2-methyl-l,3-dithiane, BuLi, THF, -25 °C [85%] (e) Hg(C10 4) 2, CaCQ3, H 2 0 , T H F [93%] (f) T B A F , THF, reflux [90%] (g) (COClfe, D M S O , C H 2 C 1 2 , -78 °C; EtjN, - 7 8 ° C — > r . t [95%] (h) 1 0 % K O H , M e O H ; M s C l , D M A P , E t 3 N ( C H 2 C l 2 , 0 ° C ; D B U [82%] (i) l M H C L M e ^ O [90%] (j) NaBRj , MeOH, -10 °C [85%] (k) H 2 , Pd-C, EtOH [95%] Scheme 2.14. Conversion of (-)-Ketal-Ester 164b to the Helenanolide Relay Compounds (-)-Ketal-enone 140 and Hydroxy-Ketone 123. 44 OTBDPS 169 168 Scheme 2.15. Stereoselective Alkylation of an Ester Bearing a Stereocenter at the j8 Position. We envisioned that the ketal-ester 164b could serve as a common intermediate in our projected routes to the helenanolides and ambrosanolides. In the helenanolide series (cf. Scheme 2.14), treatment of ketal-ester 164b with LDA in THF at -78 °C followed by addition of methyl iodide resulted in the stereoselective94 formation of alkylated ester 165. As far as could be determined by 400 MHz *H NMR, G L C , and T L C , only one diastereomer was produced as a result of this alkylation reaction. The excellent stereoselectivity94 with which this alkylation occurred was not surprising. Similar stereoselectivity had been observed previously by u s 4 5 ' 1 4 0 and others9 4 in ester alkylation reactions in which there is a stereocenter at the /3-position; Evans 9 4 b has coined the term 'extra-annular chirality transfer' to describe this phenomenon. A rationale (cf. Scheme 2.15) has been proposed to explain the stereselective alkylation. It is presumed94 that the enolate 166 formed when ketal-ester 164b is treated with L D A adopts a preferred conformation in which allylic strain between the oxide or methoxy group at C(9) and the groups at C(l) is minimized. 9 4 0 In such a preferred conformation (cf. 167), the smallest group at C(l), namely the proton, eclipses 9 4 0 or is slightly staggered943>c from the enolate double bond (cf. 167). 45 Alkylation occurs from the most accessible face of the enolate (cf. 167 —> 168) to yield the ester 168 (= 169) with the indicated C(10) configuration (Scheme 2.15).94 Attempts to confirm the predicted configuration at C(10) of 165 by means of NOE difference spectroscopy (cf. Table 5.4, p. 133) were not successful. The proximity of the C(10)-methyl proton signal (1.08 ppm) to that of the f-butyl group (1.04 ppm) in the 400 MHz *H NMR spectrum did not permit selective irradiation of the former even when low decoupler power was used. Furthermore, although it was possible to irradiate the H(10) signal selectively, the results of the NOE experiment could not be interpreted with certainty. Based on our previous experience with this stereoselective alkylation reaction we assumed for now that the correct C(10) stereochemistry, as depicted in structure 165 (Scheme 2.14), had been obtained. We elected to postpone the NOE experiment to a later, more convenient stage of the synthesis. Reduction of ester 165 with lithium aluminum hydride in THF provided ketal-alcohol 170 in 96% yield. It was important to keep the reaction temperature at or below 0 °C. When the reaction mixture was allowed to warm to room temperature after the addition of 165 to LiAlH4 was complete, a significant amount of the ketal-diol 171 resulting from cleavage of the silyl pro-tective group was isolated. This observation is consistent with results reported recently by Corey and Jones95 who have documented the ability of DIBAL to cleave silyl ethers. Conversion of alcohol 170 to the corresponding iodide 172 was accomplished uneventfully by reaction with I 2 , PPh3, imidazole in 5:3 diethyl ether-acetonitrile.96 Addition of iodide 172 to a solution of 2-lithio-2-methyl-l,3-dithiane97 in THF at -25 °C, generated by dropwise addition of butyllithium to a solution of 2-methyl-l,3-dithiane at -25 °C, yielded the ketal-dithiane 173 as a viscous, colourless oil in -85% yield. 46 Chemoselective hydrolysis of the thioketal in 173 was attempted initially using a ten-fold excess of methyl iodide and powdered calcium carbonate in aqueous acetonitrile.4 2'9 8 The calcium carbonate was added in order to neutralize any hydriodic acid that would be formed during the course of the reaction. However, analysis of the reaction mixture by T L C revealed the presence of two compounds, later separated and identified as the desired methyl ketone 174 and the diketone 175 (Equation 2.1). Attempts to minimize the formation of the undesired diketone 175 by increasing the amount of calcium carbonate or decreasing the amount of methyl iodide used were not successful. H ; H \ CH 3 I , C a C 0 3 C H 3 C N , H 2 0 yj \ 1 7 I O ' k ^ / OTBDPS 173 O + yj \ 1 7 l ^ ° o ' OTBDPS 174 (2.1) Fortunately we were able to uncover an alternative procedure that was reported by Bernardi and Ghiringhelli,9 9 who were able to hydrolyze selectively the thioketal in 176 (cf. Equation 2.2) using mercury(II) perchlorate and calcium carbonate in aqueous THF to yield the hydroxy-ketone 177. In this case, the purpose of the calcium carbonate is to neutralize any perchloric acid that is formed over the course of the reaction. Hg(Cl0 4 ) 2 , CaC03 THF, H 2 0 (2.2) 176 177 Following this procedure, an aqueous solution of mercury(II) perchlorate trihydrate (1.5 eq) was added over 5 min to a suspension of ketal-dithiane 173 (1 eq) and calcium carbonate (2.0 eq). The reaction was complete after only 5 min and gratifyingly, only one product was detected by T L C . Ultimately the desired methyl ketone 174 was isolated in excellent (93%) yield. The identity of methyl ketone 174 was confirmed by its spectral characteristics. In the 400 MHz lH NMR spectrum, the signal at 1.97 ppm (s, 3H) supports the presence of a 47 -C(0)CH3 fragment. Likewise the one-proton multiplets at 2.05-2.17 ppm and 2.61-2.71 ppm can be assigned to the diastereotopic protons at C(9). The 1 3 C NMR spectrum shows a signal at 208.9 ppm that can be assigned to the carbonyl carbon of 174, and the infrared spectrum shows a carbonyl stretching absorption at 1717 cm - 1 . The removal of the TBDPS protective group9 3 of 174 was now attempted. However, when the methyl ketone 174 was treated with a 1 M solution of tetrabutylammonium fluoride (TBAF; 2 eq) in THF and stirred at room temperature for 24 h, no reaction occurred. Likewise, treatment of 174 with ~2 M NaOH in 1:1 E t O H - H 2 0 9 3 resulted only in recovery of starting material. It was found later that when five equivalents of T B A F were used and the reaction was conducted at reflux the deprotection could be accomplished in only 3 h. The success of the procedure was evident after inspection of the infrared spectrum of the product alcohol 178. The medium-intensity absorption at 3533 c m - 1 supports the presence of a hydroxyl group in the product. Likewise the disappearance of signals found previously in the spectra of 174, namely those at 3072 and 3042 c m - 1 (aromatic C - H stretch) and 1590 c m - 1 (aromatic C=C stretch) is consistent with the loss of the TBDPS group. Subsequently, subjection of hydroxy-ketone 178 to Swern oxidation conditions100 led to the formation of keto-aldehyde 179. Of note, the infrared spectrum of 179 showed a weak absorption at 2735 c m - 1 which is characteristic101 of an aldehydic C - H stretch and a strong absorption at 1715 c m - 1 (carbonyl stretch). In the *H NMR spectrum, the diagnostic singlet at 9.72 ppm (s, 1H) is indicative of an aldehyde proton (-CHO) resonance. Treatment of keto-aldehyde 179 with 10% aqueous potassium hydroxide (3 eq) in methanol42 at room temperature resulted in an intramolecular aldol reaction to yield a single product that was suggested by T L C analysis to be more polar than the starting material. The infrared spectrum of this crude product exhibited a broad O - H stretching absorption at 3519 cm - 1 and a strong carbonyl stretching band at 1697 c m - 1 suggesting that the product that had formed was the hydroxy-ketone 180 (Equation 2.3). 4 8 180 140 The hydroxy-ketone intermediate 180 was not characterized or purified further, but was converted directly to the corresponding mesylate via standard conditions (MsCl, DMAP, Et3N, CH2CI2). The progress of the reaction was monitored by T L C , and it was found that the hydroxy-ketone 180 was converted completely to the corresponding mesylate after 1.5 h. At this point, D B U was added to the reaction mixture in order to promote dehydromesylation to afford the desired ketal-enone 140. With the successful preparation of ketal-enone 140 we have achieved the first formal, enantiospecific synthesis of the helenanolide (+)-carpesiolin (96), as Vandewalle and co-workers87 have already reported (cf. Scheme 2.6) the conversion of ketal-enone 140 to carpesiolin (96). The spectral data that we obtained for ketal-enone is in agreement with those reported previously by Vandewalle and co-workers.87 As expected, the infrared spectrum of 140 showed absorptions at 1672 c m - 1 (carbonyl stretch) and 1626 c m - 1 (C=C stretch), both of which support the presence of an a,/3-unsaturated carbonyl unit in ketal-enone 140. In the *H NMR spectrum, the doublet at S 6.40 ppm can be assigned to H(6) while the doublet of doublets at 8 5.91 ppm can be assigned to H(7). The additional multiplicity in the latter signal is due to long-range coupling of H(7) with H(9). The four protons of the ketal moiety of 140 give rise to a multiplet at 3.86-4.04 ppm. At this juncture, an attempt was made to confirm the anti relationship of the C(5) and C(10) methyl groups in 140 by means of a difference NOE experiment (cf. Table 5.7, p. 143). Originally, it was hoped that irradiation of the H(10) signal would give rise to enhancement of the intensity of the C(5) methyl signal; however, the H(10) signal formed part of the multiplet at 1.89-2.06 ppm in the 400 MHz lH NMR spectrum, and selective irradiation of H(10) was not 49 possible. Irradiation of the C(5) methyl signal at 1.12 ppm led to enhancement of signals at 1.89-2.06 ppm [H(10), H(l), and H(3)], 1.72-1.86 ppm [H(2) and H(3)], and 1.36-1.46 [H(2)J, but not the C(10) methyl signal at 1.01 ppm. Likewise, irradiation of the C(10) methyl signal did not lead to enhancement of the C(5) methyl signal. However, we are aware that the absence of an NOE between the C(5) and C(10) methyl groups does not necessarily imply that the two methyl groups are far apart from each other. Despite this reservation, we argue that in view of the fact that an NOE is observed between the C(5) and C(10) methyl groups of the epimeric ketal-enone 200 (see pp. 60-61), which differs from ketal-enone 140 only in the C(10) configuration, the absence of an NOE between the C(5) and C(10) methyl groups of 140 suggests that the C(10) methyl group of 140 must bear the alternative, namely a configuration. Noteworthy in the 75 MHz 1 3 C NMR spectrum are the signals at 8 203.4, 148.4, and 130.5 ppm, which can be assigned to C(8), C(6), and C(7), respectively. The chemical .shifts of these signals are consistent with those expected for -the - C H = C H - C ( 0 ) - unit of an a,(5-unsaturated carbonyl system. Other signals in the 1 3 C NMR spectrum were assigned with the help of a HETCOR spectrum (cf Table 5.9, p. 144). Additionally, the APT and COSY (cf Table 5.8, p. 144), and mass spectra were also consistent with those expected for 140. We recognized that it was possible to convert (-)-ketal-enone 140 further to hydroxy-ketone 123, the racemic form of which was an intermediate (cf. Schemes 2.2 and 2.9) in total syntheses of (±)-helenalin (95),83'84 (±)-bigelovin (97),88 (±)-mexicanin I (98),88 and (±)-linifolin A (99)88 by various workers. To this end, ketal-enone 140 was converted to the enedione 181 with 1 M HC1 in acetone.102 In addition to the a,/3-unsaturated carbonyl band at 1672 c m - 1 of the infrared spectrum, another peak is present at 1742 c m - 1 . This latter peak, arising from the stretching of the C(4) carbonyl group, falls in the range expected for a five-membered ring ketone carbonyl stretch. The 1 3 C NMR spectrum of 181 exhibits two signals, at 8 217.2 and 202.3 ppm, which can be assigned to the carbonyl and a,/3-unsaturated carbonyl carbons, respectively. 50 At this stage it was anticipated that it would be possible to effect a chemoselective reduction 1 0 3 of the saturated carbonyl group owing to the reduced electrophilicity of the a,/3-unsaturated carbonyl carbon. Thus, treatment of an ethanolic solution of enedione 181 at -10 °C with sodium borohydride103 led to the formation of (-)-hydroxy-enone 182 in 85% yield. Less than 5% of the enediol 183 was isolated. An infrared absorption at 3363 c m - 1 supports the presence of the newly introduced hydroxyl group while one at 1687 c m - 1 indicates the presence of an a,/3-unsaturated carbonyl group. In the 400 MHz J H NMR spectrum, the multiplet at 8 3.58-3.64 ppm can be assigned to the H(4) proton while a broad singlet at 1.62 ppm that exchanges with D 2 0 can be assigned to the hydroxyl proton. That the a,/3-unsaturated carbonyl has not been reduced by NaBH4 is indicated by the presence of the two vinyl proton signals at 6.62 ppm (d, J = 11.6 Hz, 1H) and 5.91 (dd, J = 11.6, 1.5 Hz). The chemical shifts of these two signals are in the ranges expected for vinyl protons of a,/3-unsaturated carbonyl systems. Further evidence that the reduction was chemoselective is given by the 1 3 C NMR spectrum, which shows a carbonyl carbon signal at 8 202.9 ppm. An attempt was made to confirm the configuration of the newly introduced stereocenter at C(4) using a difference NOE experiment. Irradiation of the H(4) proton [3.58-3.64 (m, 1H)] resulted in enhancement of the signals at 6.62 ppm (representing H(6)), 1.99-2.09 ppm (H(3A)), 1.82-1.98 ppm (H(10) and H(2A), collectively), 1.62 ppm (-OH), and 1.34-1.58 (H(l), H(3B), and H(2B), collectively). However, no enhancement of the singlet at 1.03 ppm, representing the C(5) methyl protons, was observed. Unfortunately, due to the proximity of the C(5)- and C(10)-methyl signals at 1.03 and 1.00 ppm, respectively, it was not possible to irradiate the former HO 183 51 signal selectively. Likewise, the presence of various overlapping multiplets in the spectrum prevented further unambiguous NOE determinations from being made. Although the absence of an NOE between H(4) and the C(5) methyl protons does not necessarily provide conclusive evidence to support the configurational assignment at C(4), we have assigned the j3-stereochemistry to the C(4) hydroxyl group in 182 on the basis of analogous1 0 3 stereoselective sodium borohydride reductions. In any case, the exact stereochemistry at C(4) in hydroxy-enone 182 is not crucial to its subsequent use in helenanolide synthesis, as there is a carbonyl group at C(4) of all the helenanolides under consideration (cf. Scheme 2.1). Finally, catalytic hydrogenation of (-)-hydroxy-enone 182 (H2, 10% Pd-C, EtOH) led to the formation of hydroxy-ketone 123. As expected, the infrared spectrum of (-)-hydroxy-ketone 123 exhibits a hydroxyl stretching vibration at 3420 cm - 1 . The carbonyl stretching vibration that was present at 1687 c m - 1 in the infrared spectrum of the starting (-)-hydroxy-enone (182) now shifts to 1695 c m - 1 . Most notable in the 400 MHz *H NMR spectrum is the absence of peaks between 4.5-7.0 ppm, supporting the fact that there are no vinyl protons in 123. The multiplet at 3.60-3.66 ppm can be assigned to the C(4) proton, which is deshielded by the presence of the geminal, C(4)-hydroxyl group. The 75 MHz 1 3 C NMR,-APT, and mass spectral data, also, are consistent with those expected for (-)-hydroxy-ketone 123. Racemic hydroxy-ketone 123 and its tetrahydropyranyl ether derivative have been converted previously to the bicyclic dienone 110 and in turn, to (±)-helenalin (95) (cf. Scheme 2.2) by Roberts and Schlessinger.82 Likewise, the benzyl analogue of 110 has been converted to (±)-bigelovin (97),88 (±)-mexicanin I (98),88 and (±)-linifolin A (99)88 by Grieco and co-workers (cf. Schemes 2.2 and 2.9). Our enantiospecific synthesis of (-)-hydroxy-ketone 123 from (-)-camphor (ent-9) therefore constitutes the first formal synthesis of (-)-helenalin (95), (+)-bigelovin (97), (+)-mexicanin I (98), and (+)-linifolin A (99). It follows that the enantiomers of these natural products could be prepared if (+)-camphor (9) were used as the starting material instead. 52 (d) An Enantiospecific Synthesis of Ambrosanolides The versatility of our synthetic route to pseudoguaianolides is demonstrated by the fact that the same (-)-ketal-ester 164b that was used in our helenanolide synthesis (cf. Scheme 2.14) can serve as an intermediate in a proposed route to the ambrosanolides as well. Access to the ambrosanolide series was gained through a reaction sequence (cf. Scheme 2.16) that starts with the stereoselective alkylation of (-)-ketal-ester 164b with allyl bromide to obtain ester 184. Once again, as far as could be determined by 400 MHz J H NMR spectroscopy, G L C , and TLC, only one diastereomer was formed through this alkylation reaction. The rationale for the high (>99%) diastereoselectivity94 has already been addressed (cf. Scheme 2.15). As in the helenanolide case, because of difficulties in irradiating protons whose chemical shifts were close together, determination of the C(10) configuration by NOE difference spectroscopy (cf. Table 5.11, p. 150) was postponed to a later stage of the project. Drawing on our previous experience with the stereoselective alkylation reaction, it was assumed for now that the C(10) configuration was the same as that predicted (cf. Scheme 2.15), and represented by structure 184 in Scheme 2.16. Treatment of ester 184 with lithium aluminum hydride at 0 °C provided ketal-alcohol 185 in excellent (-95%) yield. As before (cf. conversion of 165 to 170, Scheme 2.14, p. 43) the reduction reaction could not be carried out chemoselectively at room temperature because of a competing desilylation reaction. Mesylation of 185 using the standard procedure (MsCl, DMAP, Et3N, C H 2 C I 2 , 0 ° C ) 4 2 yielded ketal-mesylate 186. Subsequent reductive removal 1 0 4 of the 53 ^ « / 200 ~ 202 158 128 ( a ) L D A , T H F , - 7 8 0 C ; H 2 C = C H C H 2 B r , - 7 8 0C—>r.t. [95%] (b) L i A l H 4 , THF, 0 °C [96%] (c) MsCl, D M A P , E t 3 N , C H 2 C 1 2 , 0 °C [97%] (d) L iEt 3 BH, THF; 3 M NaOH, 30% H 2 0 2 [88%] (e) PdCl 2 , CuCl , 0 2 , D M F - H 2 0 ( 9 : 1 ) [91%] (f) T B A F , THF, reflux [90%] (g) (COCl) 2 , D M S O , C H 2 C 1 2 , -78 °C; E t 3 N , _78 °C—>r.t [95%] (h) 10% K O H , MeOH, 12-16 days; MsCl, D M A P , E t 3 N , C H 2 C 1 2 , 0 °C; D B U [70%] (i) l M H C l , M e 2 C O [90%] (j) NaBH4, MeOH,-10 °C [87%] (k) H 2 , P d - C , E t O H [93%]. Scheme 2.16. Conversion of (-)-Ketal-Ester 164b to the Ambrosanolide Relay Compounds Hydroxy-Enone 158 and Hydroxy-Ketone 128. mesyloxy group with two equivalents of lithium triethylborohydride (SuperHydride®) solution in THF followed by oxidative work-up (NaOH, H2O2) yielded the ketal-alkene 187. It has been suggested by Holder and Matturro1 0 4 that the second equivalent of LiEt3BH is necessary in this reaction because the triethylborane that is formed after initial reaction of the mesylate 186 with LiEt3BH reacts with a further equivalent of LiEt3BH to yield an unreactive complex with stoichiometry Et6B2H~ L i + . 1 0 4 Regardless, this deoxygenation reaction proceeded in high yield to afford the ketal-alkene 187 with a presumed (105) configuration. Conversion of the terminal alkene moiety in 187 to a methyl ketone group was accomplished by application of the Wacker oxidation. 1 0 5 Although the Wacker process 54 (Equation 2.4) was developed originally in 1958 as an industrial process for converting ethylene to acetaldehyde,106 the reaction has found considerable utility in the hands of synthetic chemists. H H P d C b . C u C h 0 >=< + o.5 o2 —hr2-* A (2-4> H H H 2 0 H 3 CT H In one example (Scheme 2.17) drawn from a synthesis of (+)-19-nortestosterone by Tsuji and co-workers,1 0 7 subjection of the enone 188 to Wacker oxidation conditions yielded the keto-enone 189 which was converted to (+)-19-nortestosterone (190) in two more steps. OBu' O ' (±)-19-nortestosterone (190) Scheme 2.17. Synthetic Utility of the Wacker Oxidation. Tsuji etal.: Total synthesis of (±)-19-Nortestosterone (190).107 Although the exact mechanism of the Wacker oxidation is still debatable, a catalytic cycle has been proposed (cf. Scheme 2.18)108 in which initially the palladium(II) salt 191 coordinates with the terminal olefin to give an (r/2-olefin)palladium(II) complex 192. Attack of water at the more substituted position of the olefin yields a cr-(hydroxyalkyl)palladium complex 193. Subsequent /3-hydride elimination occurs to provide the coordinated (772-enol)palladium complex 194, which decomposes to yield the methyl ketone 195, HC1, and palladium metal. The palladium metal thus formed can be re-oxidized to palladium(II) using a suitable oxidant. One such oxidant that is commonly used is copper(II) chloride. The reactions that are operative in the re-oxidation process are presented in Scheme 2.18. In practice, copper(I) chloride is initially oxidized with oxygen gas* to yield copper(II) chloride. Although one could start with the copper(U) salt direcdy, it has been reported, however, that the use of the copper(U) *So that the nomenclature throughout this thesis remains consistent, the molecule O2 is named 'oxygen' rather than 'dioxygen.' It is recognized, however, that the latter name is preferred in the inorganic and organometallic literature. 55 salt can lead to chlorination of the carbonyl compound formed from the Wacker reaction. 1 0 5 3 Copper(II) chloride reacts with palladium(O) metal to yield the palladium(II) salt, and in the process, copper(II) chloride is converted back to copper(I) chloride. Scheme 2.18. Proposed Mechanism of the Wacker Oxidation [N.B. Solv = solvent].108 In our synthesis of the ambrosanolides, a solution of ketal-alkene 187 (1 eq) in 9:1 D M F -H2O was added to a suspension of PdCl2 (0.2 eq) and CuCl (1 eq) in 7:1 DMF-HbO, and the reaction mixture was stirred under an oxygen atmosphere. The product, methyl ketone 196, was isolated in ~85% yield. Spectroscopic data obtained for the Wacker oxidation product are consistent with those expected for silyloxy-ketone 196. The infrared spectrum shows a strong absorption at 1716 c m - 1 while the 1 3 C NMR spectrum exhibits a signal at 5 209.0 ppm, both of 56 which support the presence of a carbonyl group in 196. Furthermore, a singlet at 8 2.09 ppm of the ! H NMR spectrum of the product is diagnostic of a CH3CXC))- subunit. From this point on it was planned to complete the synthesis according to a plan similar to that outlined earlier in our helenanolide synthesis. Silyloxy-ketone 196 was subjected to the same desilylation conditions that had been worked out for the corresponding aldol reaction in the helenanolide series (namely the conversion of 174 to 178, Scheme 2.14). Thus, reaction of silyloxy-ketone 196 with TBAF (5-10 eq) at reflux afforded hydroxy-ketone 197 in 95% yield. The identity of this product was supported by the presence of an O - H stretch at 3534 c m - 1 in the infrared spectrum and the absence of signals in the region of the X H NMR spectrum in which aromatic proton signals are expected. Swern oxidation 1 0 0 of hydroxy-ketone 197 gave the air-sensitive keto-aldehyde 198. Subjection of keto-aldehyde 198 to conditions used previously for the corresponding reaction in the helenanolide series (excess 10% KOH, MeOH, 2 h) led, quite unexpectedly, to the total recovery of starting material. Puzzled by the failure of the aldol reaction, we studied the effect of varying the K O H concentration and stoichiometry.109 In some cases, T L C suggested the formation of a product that was more polar than the starting keto-aldehyde 198. Even so, product conversions were unacceptably low (<10%). At this point we decided to re-examine the body of spectroscopic evidence we had obtained for keto-aldehyde 198. The infrared spectra of 198 shows a weak absorption at 2731 cm- 1 that can be assigned to the stretching of the aldehydic C - H bond. A broad absorption at 1718 c m - 1 supports the presence of a carbonyl group in 198; however, it was not possible to discern separate peaks for stretches due to the aldehyde or ketone carbonyl groups. Normally, aldehyde carbonyl stretching bands are found between 1720-1740 c m - 1 while ketone carbonyl stretching bands are found between 1700-1725 cm - 1 . In the 400 MHz *H NMR spectrum the singlet at 9.48 ppm arises from resonance of the aldehydic proton. The singlet at 2.12 ppm can be assigned to the protons of the terminal acetyl unit while the two singlets at 1.07 and 0.69 ppm can be assigned to the methyl groups at C(5) and 57 C(10), respectively. The presence of a multiplet at 3.69-3.85 ppm confirms that the ethylene ketal moiety is still present in 198 and has not been inadvertently hydrolyzed during intervening chemical operations. With the aid of a COSY spectrum (cf. Table 5.13, p. 159) the remainder of the spectrum could be assigned to protons at C(l), C(2), C(3), C(9), and C(10). Of note in the 75 MHz 1 3 C NMR spectrum are the two signals at 5208.2 and 207.5 ppm that support the presence of the ketone and aldehyde carbonyl groups, respectively, in keto-aldehyde 198. The APT and mass spectral data also confirm unambiguously that we have indeed synthesized the correct product, the keto-aldehyde 198. We turned our attention back to our aldol cyclization problem and sought an explanation for this recalcitrant reaction. After examining a molecular model of 198, we speculated that in order for intramolecular aldol reaction to occur, the enolate generated upon treatment of keto-aldehyde 198 with base adopts a conformation similar to that depicted by 198a in Equation 2.5. However, in the process of attaining this conformation 198a, the two methyl groups at C(5) and C(10) approach each other, resulting in an unfavorable steric interaction. Consequently, the equilibrium shown in Equation 2.5 favors 198a, and not 199. It is pertinent to note that in the corresponding reaction in the helenanolide series (179 -» 180; cf. Equation 2.3, p. 48) the configuration at C(10) of 179 is reversed. Consequently the C(5)-C(10) interaction encountered in the transformation of 179 -» 180, en route to enone 140, involves only a methyl group and a proton, and is not as severe as the l,3-sy«-dimethyl interaction encountered here in the transformation of 198a —> 199 (Equation 2.5). We were aware that if the aldol reaction were conducted at elevated temperatures then it would be possible to obtain the thermodynamically more stable a,/3-unsaturated ketone.1 0 9 We (2.5) 198a 199 58 thought if we could promote enone formation the overall reaction equilibrium would be driven further to product formation. Consequently we carried out the aldol reaction, using 2% aqueous K O H in refluxing methanol, for 24 h. This time, T L C analysis of the product mixture indicated that in addition to recovered starting material (~80%), there were two additional products. The first, isolated in ~10% yield was more polar than the starting keto-aldehyde 198 and had the same T L C R/ value of the polar product observed originally (cf. p. 56). This polar product was identified as the intermediate hydroxy-ketone 199 (cf. Scheme 2.19) on the basis of its infrared and *H NMR spectrum. The second product, also isolated in ~10% was slightly less polar than the starting material and was determined spectroscopically to be the desired ketal-enone 200. Attempts to increase the amount of enone formed by prolonging the reaction, to as long as three days, were not successful. By changing the solvent from methanol (bp 65 °C) to ethanol (bp 78 °C) it was possible to obtain a marginally better, but still unacceptable product yield of ~20%. At this time we began to explore the use of other reagent combinations109 that had been documented in the literature. Initially we investigated the use of NaOH, K O H , and B114NOH (Triton-B®) in ether solvents such as THF, DME, and diglyme. 1 0 9 In general the results of these experiments were similar to those reported above in that the problem of low reaction efficiency still persisted. Interestingly, when B114NOH (40% solution in water) was used in refluxing D M E or diglyme, it was possible to isolate a 6:1:1.5 mixture (by weight) of the starting material (198), ketal-enone 200, and a product whose T L C R/ values in a number of solvent systems were just slightly greater than that of the desired ketal-enone 200. Examination of this new product by infrared spectroscopy revealed no absorptions above 3000 c m - 1 and an absence of the aldehydic C - H stretch previously observed in the starting material at 2731 c m - 1 . However, the presence of an absorption at 1688 c m - 1 suggested the presence of an enone carbonyl in this yet unknown structure. The 400 MHz J H NMR spectrum exhibited a doublet at 6.48 ppm, which falls in the range expected normally for the /3-proton of an a,/3-unsaturated carbonyl system.1 0 1 A multiplet between 3.85-4.02 ppm can be assigned to the protons of the ethylene ketal unit. The three-59 proton singlet at 2.28 ppm is in the range expected for a methyl group adjacent to a carbonyl group. Signals at 1.13 ppm (d, J = 7.5 Hz, 3H) and 1.05 (s, 3H) suggest the presence of two other methyl groups in the molecule. With the aid of a COSY spectrum (cf. Table A.3, p. 230) it was determined that these data were consistent with those expected of the strained, substituted trans-fused bicyclo[3.3.0]octene 201 (cf. Scheme 2.19). That a strained trans-fused bicyclo[3.3.0]octene system was formed unexpectedly is not a precedent, however. Other examples of synthesized trans-fused bicyclo[3.3.0]octane derivatives can be found in the literature.110 A rationale (cf. Scheme 2.19) can be advanced to explain the formation of 202 in this case. When keto-aldehyde 198 (pKa ( a protons) ~ 20) and hydroxide (pA"a (H2O) = 15.7) are mixed, proton abstraction occurs initially at the more accessible position (that is, at C(7)) to provide the 'kinetic' enolate 198a. Equilibration of enolate 198a with unreacted keto-aldehyde 198 results in the formation of the more substituted, 'thermodynamic' enolate 198b. The aldol reaction of the kinetic enolate 198a, followed by protonation, results in the formation of a hydroxy-ketone 199a in which there is a 1,3-syn-dimethyl interaction between the C(5) and C(10) methyl groups. On the other hand, aldol reaction of the thermodynamic enolate 198b, followed by protonation, results in the formation of a hydroxy-ketone 199b in which there is a similar steric interaction as well as additional ring strain 1 1 0 a - c that arises from the trans-fused bicyclo[3.3.0]octane ring system. Thus, it is presumed that at low temperatures (e.g. room temperature), only the equilibria leading to the formation of 199a are favored, and those leading to 199b are disfavored. By contrast, at elevated temperatures, the dehydration reactions of 199a and 199b to yield the thermodynamically more stable enones 200 and 201, respectively, are both favored. A number of other reaction conditions were also evaluated, including 1 % KOH/Et20; 1 1 1 N a O M e / M e O H ; 1 0 9 K O B u ' / H O B u ' ; 1 1 2 L U / E t 2 0 ; 1 1 3 Et2A10Et/toluene;1 1 4 NaH, toluene; 1 1 5 3 , 1 1 6 p - T s O H / C 6 H 6 ; 1 1 5 a PPTS/C6H6; 1 1 5 b H3B 03/toluene;117 HOAc/piperidine/CsHe; 1 1 8 and H C l / H O A c . 1 1 9 All of these methods failed to promote the required intramolecular aldol reaction or condensation in acceptable efficiency or yield. As a related example, an unsuccessful attempt 60 by Klipa and Hart to prepare bicyclo[3.3.0]oct-4-en-3-one via aldol condensation (5% K O H , EtOH, reflux) has been documented.116 Scheme 2.19. Competing Aldol Condensation Pathways of Keto-aldehyde 198. Finally, after considerable experimentation it was found that treatment of a ~0.1 M solution of keto-aldehyde 198 with 10% aqueous K O H (~5 eq) followed by reaction for 12-16 days at room temperature resulted in the successful production of hydroxy-ketone 199 with minimal starting material (<5%) remaining, as detected by G L C . Crude hydroxy-ketone 199 was not purified but was converted directly to ketal-enone 200 via a mesylation (MsCl, Et3N, DMAP, CH2CI2, 0 °C)-dehydromesylation (DBU, CH2CI2) sequence. Ultimately, ketal-enone 200 was obtained in 70% yield from keto-aldehyde 198. The syn relationship between the C(5) and C(10) 61 methyl groups in ketal-enone 200 was confirmed by the results of an NOE experiment [400 MHz] in which irradiation of the C(5) methyl signal (1.19 ppm) resulted in enhancement of the C(10) methyl signal (1.07 ppm), and vice versa. The completion of the ambrosanolide synthesis followed a plan analogous to that described previously for the synthesis of helenanolides. Thus, ketal-enone 200 was deprotected with 1 M HC1 in acetone102 to yield enedione 202. Stereo- and chemoselective reduction (NaBH4, EtOH, -10 ° C ) 1 0 3 of the C(4) carbonyl group yielded hydroxy-enone 158 as a single diastereomer; no traces of the alternative C(4) diastereomer was detected or isolated. Finally, catalytic hydrogenation of 158 (H2, 10% Pd-C, EtOH) provided the (-)-hydroxy-ketone 128. All of these reactions proceeded uneventfully and in high yield. Attempts to determine the C(4) configuration of 158 or 128 through NOE experiments (cf. Table 5.14, p. 164) were met with difficulties similar to those described earlier (cf. pp. 50-51), although in the case of 128, selective irradiation of both H(4) [3.60 ppm] and the C(5)-methyl [0.70 ppm] signals was possible. No NOE was observed between H(4) and the C(5)-methyl signals. Ultimately, the C(4)-hydroxy group was assigned a ^ -configuration on the basis of arguments similar to those made earlier for hydroxy-enone 182 (cf. pp. 50-51). Hydroxy-ketone 128 has been converted previously to confertin (102) while the r-butyl ether of 128 has been converted to (±)-damsin (103) by Quallich and Schlessinger (cf. Scheme 2.3). Thus, our synthesis of hydroxy-enone 158 and hydroxy-ketone 128 represents a formal, enantiospecific synthesis of (+)-confertin (102) and (-t-)-damsin (103). Spectroscopic data for all relay compounds (viz. 140, 123, 103, and 102) were in agreement with those reported previously in the literature. 8 3 ' 8 5 ' 8 6 - 8 8 Minor modifications of the two routes to the helenanolides and ambrosanolides presented in this chapter120 could lead to the enantiospecific synthesis of other pseudoguaianolides and their analogues. It is envisaged, for example, that protection of the hydroxyl group of ketal-alcohol 185 (Scheme 2.16) will provide an intermediate that could be of value in a projected synthesis of enantiopure hysterin (203).80b In summary, the syntheses of hydroazulenoid ketones 140,123,103, and 102 (Scheme 2.11) 62 from (-)-camphor (ent-9) represent formal syntheses of (+)-carpesiolin (96), (-)-helenalin (95), (+)-bigelovin (97), (+)-mexicanin I (98), (+)-linifolin A (99), (-)-damsin (158), and (+)-confertin (128).120 O hysterin (203) Chapter 3 An Enantiospecific Synthetic Approach to the Limonoids 64 3. An Enantiospecific Synthetic Approach to the Limonoids1W (a) Introduction The limonoids1 2 1 are a group of complex, structurally diverse tetranortriterpenoids found generally in plants belonging to the Meliaceae, Rutaceae, and Cneoraceae families. Some representative limonoid structures are given in Scheme 3.1. Many members of this family of compounds display anti-malarial, insect antifeedant or insecticidal properties. 1 2 1 ' 1 2 2 Biosynthetically,121a the limonoids are believed to be derived from the triterpenoids euphol (204; cf. Scheme 3.2) and tirucallol (205) through the loss of a four-carbon unit. Euphol (204) and tirucallol (205), in turn, are derived from 2,3-oxidosqualene (206). A possible biogenesis of the limonoids is outlined in Scheme 3.2. Cyclization of 2,3-oxidosqualene (206) yields a tetracyclic alcohol 207 which is transformed into euphol (204) and tirucallol (205) after a series of proton and methyl shifts. Subsequently, euphol (204) and tirucallol (205) are converted to apo-euphol (208) and apo-tirucallol (209). Although the exact biosynthetic route to the limonoids is unknown, it has been speculated that apo-euphol (208) and apo-tirucallol (209) are converted first to a protolimonoid intermediate, in which the C(20)-side chain is highly oxidized. The compounds grandifolioenone (212) and glabretal (213) are representative examples of protolimonoids. Subsequently, the loss of a four-carbon unit from the protolimonoid side chain followed by the formation of a 3-furyl substituent at C(17) leads to the formation of a tetracyclic limonoid such as azadirone (214) or azadiradione (215). O H O' grandifolioenone (212) glabretal (213) azadirone (214) azadiradione (215) Scheme 3.1. Structures of Representative Limonoids. 66 (206) 204: euphol (20(#); X=H, Y=CH 3 ) 208: (20(A); X=H, Y=CH 3 ) 205: tirucallol (20(5); X=CH 3 , Y=H) 209: (20(5); X = C H 3 , Y=H) LIMONOID 210: 7a-hydroxy-apo-euphol (X=H, Y=CH 3 ) 211: 7a-hydroxy-apo-tirucaUol (X=CH 3 , Y=H) Scheme 3.2. Proposed Biogenesis of the Limonoids. 1 2 1 3 Further structural modifications can occur, as illustrated by the diverse structures presented in Scheme 3.1. In many cases, further oxygenation can occur at various positions in the basic limonoid skeleton. Epoxidation of the C(14)-C(15) double bond is common and the A and D rings can undergo Baeyer-Villiger-type oxidation to produce lactone rings [cf. limonin (216), gedunin (218), mexicanolide (220), and obacunol (222)]. On the other hand, the B and C rings can be cleaved to yield seco-limonoid derivatives [cf. andirobin (219), nimbin (223), prieuranin (226), and azadiractin (227)]. These modifications can take place either singly or in combination, and ultimately give rise to limonoids of considerable structural complexity. 67 (b) Previous Synthetic Routes to Limonoids and Analogues Literature reports concerning synthetic approaches to limonoids and limonoid model systems remain generally scarce. It is perhaps due to the structural complexity of the limonoids that no total synthesis of members of this family has been documented until mid-1989 when Corey and co-workers published a total synthesis of (±)-azadiradione (215) starting from trans, trans-fdxnesol (228; Scheme 3.3).123 trans, trans-Famzsol (228) was converted in three steps to the tetraenol phosphate 229. Treatment of 229 with mercury(II) trifluoroacetate in nitromethane promoted a polyolefin cyclization reaction to provide tricyclic keto-ester 230. The chloromercurio group in 230 was replaced by a hydroxyl group upon treatment with oxygen gas in the. presence of sodium borohydride in DMF, and subsequent Jones oxidation yielded the diketo-ester 231. The preparation of the allylic alcohol 232 from 231 was achieved through standard reactions. Installation of a 7a-hydroxyl group was accomplished via application of Barton's method and proceeded through the intermediate hemiketal 233. Hydrolysis of the hemiketal followed by selective reduction of the C(7)-keto group yielded keto-diol 234. Conjugate addition of the sodium salt of 3-(2-nitroethyl)furan to the a,/J-unsaturated ketone generated in situ from 234 and subsequent Nef reaction afforded the hydroxy-triketone 235. Intramolecular aldol condensation of 235 yielded the tetracyclic enone 236. Subsequent conversion to the allylic alcohol 237 was carried out via conventional means. Hydroxyl-directed cyclopropanation of the allylic alcohol 237 followed by Dess-Martin oxidation yielded the diketone 238. Installation of the C(13)-methyl group was accomplished via dissolving metal mediated opening of the cyclopropyl ring. A further Dess-Martin reaction yielded diketone 239. a-Phenylselenenylation of 239 followed by oxidation and selenoxide fragmentation led to the formation of bis-enone 240. Finally, replacement of the methoxyethoxymethyl protective group with an acetyl group completed the total synthesis of (±)-azadiradione (215).123 According to Corey and co-workers, 1 2 3 azadiradione (215) has been converted previously to several other tetracyclic limonoids and therefore, their synthesis of azadiradione constitutes a formal synthesis of other limonoids. 68 (a) MsCl, E t 3 N , C H 2 C 1 2 , -20 °C (b) LiBr, T H F , - 2 0 °C (c) methyl acetoacetate sodio and lithio dianion, T H F ; (EtO) 2POCl, - 7 8 - » -20 °C (d) HgfOzCO^fe, C H 3 N 0 2 , 0 °C; aq. NaCl (e) 0 2 , NaBH*, D M F ; 1 N H 2 S 0 4 , 1 0 °C (£) Jones reagent, 0 °C (g) NaH, THF, reflux; (EtO) 2POCl, 0 °C (h) ( C H 2 O H ) 2 , p-TsOH, Q H 6 , reflux (i) DIBAL, P h C H 3 , -20 °C; aq. HC1, MeOH (j) H 0 3 S O N O , C 5 H 5 N , 0 °C; MeOH (k) hv, C H 2 C 1 2 , 50 °C; separation of aldehyde (1) 1 N H C 1 , C H 3 C H 0 (m) Me4N + "B(OAc) 3 H, M e 2 C O , H O A c , - 7 8 °C (n) Na + ~CH(N0 2 )-CH 2 -(3-furyl), EtOH, reflux (0) 12 N HC1, EtOH, 10 °C (p) NaOEt, EtOH, 70 °C (q) M E M - B r , TBAI, Pr' 2NEt, C H 3 C N , 70 °C (r) L i B u ^ B H , THF, -78 °C (s) D E A D , PPh 3 , T H F , P h C 0 2 H (t) NaOH, EtOH (u) C H 2 I 2 , Z n - A g , 0 °C (v) Dess-Martin periodinane, C H 2 C 1 2 (w) L i , N H 3 (x) L D A , THF, -78 °C; PhSeBr; 30% H 2 0 2 , H 2 0 - C 5 H 5 N , warm (y) Me 3SiBr, CH 2 C1 2 , - 20 °C (z) A c 2 0 , D M A P , T H F . Scheme 3.3. Corey and Hahl: Total Synthesis of (±)-Azadiradione. 1 2 3 69 In the subsequent year, Fernandez Mateos and de la Fuente Blanco reported the synthesis of bicyclic enone 241a and bicyclic epoxy-lactone 242 (Scheme 3.4).1 2 4 Due to the structural similarity of 241a and 242 to the C,D-ring system of azadiradione (215) and gedunin (218; Scheme 3.1), respectively, the authors suggested that 241a and 242 could be used to probe the structure-activity relationships in limonoids. Their approach is summarized in Scheme 3.4 and started with the stereoselective addition of (£)-l-(3-furyl)-2-nitro-l-propene to the trimethylsilyl enol ether 243 to provide as the major diastereomer the bicyclic silyl nitronate 244. Hydrolysis of 244 followed by a Nef reaction and aldol condensation yielded a 4:1 mixture of epimeric enones 241a and 241b, respectively. The 17a-epimer (241a) was separated and converted further to the epoxy-lactone 242 after reduction, epoxidation, Jones oxidation, and Baeyer-OSiMe, 243 244 o (a) (£)-l-(3-furyl)-2-nitropropene,TiCl4,CH 2 Cl 2 , -78 0 C (b) K O H , EtOH (c) K O H , EtOH, 86 °C, separation of 17/3-furyl diastereomer (d) LiAlH4, E t 2 0 , 0 °C (e) m-CPBA, C H 2 C 1 2 , -40 °C (f) Jones reagent, acetone, 0 °C (g) m-CPBA, CH 2 C1 2 . 241a: 17afuryl 241b: 17/Jfuryl d - g J 9 242 Scheme 3.4. Fernandez Mateos and de la Fuente Blanco: Synthesis of Limonoid Analogues 124 Villiger oxidation steps. Recent papers1 2 5 from the same research group present alternative syntheses of enone 241a in which the use of an intramolecular diazo-ketone cyclization is featured. In addition, a further report1 2 6 from the Fernandez Mateos group describes the formal synthesis of (±)-pyroangolensolide (246; cf. Scheme 3.5), a bicyclic, unsaturated lactone1 2 7 that is derived from the pyrolysis127c>d of natural methyl angolensolate (225, Scheme 3.1). 70 a ^ r ^ S ^ O H b,c r ^ f ^ O OSiMe3 S r ^ O l o i l ^ 0 247 248 249 250 (+)-pyroangolensolide (246) (a) 3-furaldehyde, T i C l 4 , , CH 2 C1 2 , -78 °C (b) A c 2 0 , C5H5N, 0 °C (c) L D A , Et 2 0 , -78 °C (d) S0C1 2 , C 5 H 5 N (e) NBS, CCI4 (f) K 2 C 0 3 , MeOH Scheme 3.5. Fernandez Mateos and de la Fuente Blanco: Synthesis of (±)-Pyroangolensolide. 1 2 6 Lhommet and co-workers have reported an alternative approach to the Fernandez Mateos bicyclic epoxy-lactone 242. 1 2 8 The synthesis, summarized in Scheme 3.6, involves the initial conversion of the Wieland-Miescher ketone analogue 251 to bicyclic ketone 252. Addition of 3-(dichlorocerio)furan to ketone 252 followed by dehydration and osmium tetroxide mediated dihydroxylation provided diol 253. Subsequent pinacol rearrangement128 of 253 and acid-a—e f—h 254 J—m (a) 2-ethyl-2-methyl-l,3-dioxolane,/?-TsOH (b) H 2 , Pd-C, EtOH (c) N a H , T H F , reflux; CH3I (d) N H 2 N H 2 . H 2 0 , K O H , diethylene glycol, 210 °C (e) /?-TsOH, M e 2 C O (0 3-bromofuran, n-BuLi; anh. C e C l 3 , T H F (g) MsCl, E t 3 N, C H 2 C 1 2 (h) O s 0 4 , N M O , Me2CO, H 2 0 (i) p-TsOH, C 6 H6, reflux (j) m-CPBA, N a H C 0 3 , CH 2 C1 2 —C1CH 2 CH 2 C1 (k) /-BuLi, PhSeSePh, T H F - H M P A , -78—>0 °C (1) m-CPBA, C H 2 C 1 2 , 0 °C (m) H 2 0 2 NaOH, M e O H 242 Scheme 3.6. Lhommet et al.: Synthesis of a Limonoid Intermediate.128 catalyzed epimerization128 yielded the ketone 254. Baeyer-Villiger oxidation followed by introduction of the C(14)-C(15) double bond (triterpenoid numbering) and enone epoxidation 71 completed the synthesis of racemic epoxy-lactone 242. If desired, however, the enedione 251 that was used as a starting material in this synthesis could be obtained in enantiopure form 1 2 8 and the synthesis of 242 could therefore be considered enantiospecific. Finally, extensive investigations by Ley and co-workers122 have been directed towards a total synthesis of azadirachtin (227) and structural analogues. Due to space constraints in this thesis, this large body of work will not be summarized. In 1992 our research group published an enantiospecific synthesis of bicyclic enone-ester 255 from (+)-camphor (9).45 Our interest in the area of limonoid synthesis resulted from our recognition that enone-ester 255 and its enantiomer (ent-255) has considerable potential as C D -ring intermediates in steroid and triterpenoid synthesis, respectively. In particular, we noted that the relative and absolute configurations of the two stereocenters of ent-enone ester (ent-255), at C(13) and C(17) are identical to those found in the tetracyclic limonoids. C 0 2 M e 255 In devising a preliminary synthetic strategy we considered azadiradione (215) as our initial target molecule. Concern for the lability of the furan moiety in 215 under acidic and oxidative conditions129 prompted us to defer the construction of the furan ring to a relatively late stage in our synthetic plan (cf. Scheme 3.7). With this consideration in mind, we envisioned that the target limonoid, azadiradione (215), could be derived from an advanced, tetracyclic intermediate such as bis(alkoxy)-dienone 256. In turn, dienone 256 could be derived from the tricyclic enone 257 through appropriate annulation and alkylation procedures. Finally, enone 257 could arise from the known e/ir-enone-ester (ent-255), which can be prepared conveniently from (-)-camphor (ent-9) or (-)-borneol (159). Our progress in this area is documented in the remainder of this chapter. 72 azadiradione (215) „OMe OMe H,CT OMe ^ C 0 2 M e (-)-camphor (ent-9) ent-255 Scheme 3.7. Synthetic Plan for a Proposed Limonoid Synthesis. (c) Results and Discussion L Preparation of Bicyclic Enone 267 from (-)-Camphor fent-9) In the first stage of our synthetic approach to the limonoids we needed to prepare ent-enone-ester (ent-255)45 in sufficient quantities. For this purpose we needed to employ (-)-camphor (ent-9) as our starting material, and as mentioned previously (p. 40), this could also be O H (-)-borneol (159) Scheme ^ (-)-camphor (ent-9) • C 0 2 M e ^ C 0 2 M e ^ C 0 2 M e O H C ^ ^ c M e 0 2 C v ^ s ^ ^ 160 258 20^.CO 2 Me • C 0 2 H 13 O 114 8 "15 ent-155 259 • C02M<J| Me°2Cv^^o 261 260 (a) C r 0 3 , aq. H 2 S 0 4 , acetone, 0 °C [97%] (b) (C0C1)2, DMSO, CH 2 C1 2 , -78 °C; E t 3 N , -78 °C -> r.t. [92%] (c) (MeO) 2P(O)CH 2C02Me, NaH, T H F [96%] (d) Mg, MeOH, 0 °C (e) K O H , H 2 0 , MeOH [86%, from 259] (f) (CF 3 CO) 2 0 , CH 2 C1 2 ; p-TsOH, MeOH [89%]. Scheme 3.8. Preparation of Bicyclic (-)-Keto-enone (ent-255).38<39'45 prepared via Jones oxidation of (-)-borneol (159). (-)-Camphor (ent-9) was then converted to (+)-hydroxy-ester (160) via the six-step route 3 8 ' 3 9 ' 4 5 described earlier in this thesis (Scheme 2.12). 73 Swern oxidation1 0 0 of (+)-hydroxy-ester 160 (Scheme 3.8) provided the ester-aldehyde 258. Treatment of aldehyde 258 with the sodium salt of trimethyl phosphonoacetate (Horner-Wadsworth-Emmons reaction)130 yielded the a,/3-unsaturated ester 259 as a single diastereomer. The large coupling constant (J = 16.0 Hz) between the two olefinic protons at C( l l ) and C(12) (triterpenoid numbering) suggested101 that the double bond had been formed with an (£ ) or trans stereochemistry. Subsequent chemoselective reduction of the unsaturated ester 259 with magnesium in methanol1 3 1 yielded, presumably, the intermediate diester 260 which was not isolated, but hydrolyzed directly with aqueous potassium hydroxide solution to yield diacid 261. Treatment of the crystalline diacid 261 with trifluoroacetic anhydride (2 eq.) in dichloromethane132 effected a cyclization reaction to afford the bicyclic enone-acid 261a, which can be isolated if desired. However, if the dichloromethane solvent is removed by evaporation and replaced with dry, distilled methanol, then subsequent addition of p-toluenesulfonic acid promotes a further esterification reaction and the product that is isolated under these circumstances is the bicyclic enone-ester ent-255. Spectroscopic data obtained for the enone-ester ent-255 prepared above were consistent with those reported previously in the literature. Thus, the presence of two carbonyl stretching absorptions at 1740 and 1662 c m - 1 support the presence of an ester group and an a,/J-unsaturated ketone group, respectively. Similarly, the two signals in the 50 MHz 1 3 C NMR spectrum at 198.7 and 177.5 ppm further confirm the presence of the enone and ester carbonyl groups, while the two signals at 173.0 and 122.0 ppm can be assigned to C(14) and C(8), respectively, which form part of the enone system. Of note in the 400 MHz J H NMR spectrum is the resonance for the C(8) enone vinyl proton at 5.80 ppm, which appears as a broad singlet. It is believed that the broadness of this signal is a result of additional long-range coupling of H(8) ^ C 0 2 H 261a 74 with one or both of the H(15) protons. Furthermore, the singlet at 3.71 ppm can be assigned to the methyl ester (-COoMe) protons while the singlet at 1.05 ppm can be assigned to the protons of the angular C(13) methyl group. The remainder of the *£! NMR spectrum, as well as the APT and mass spectra, are consistent with those expected for enone-ester ent-255. As our synthetic plan (Scheme 3.7) suggested, the next stage of the project was to add a two-carbon unit to C(20) so as to permit the future construction of a furan ring at that position. In preparation for this alkylation reaction, bicyclic enone-ester ent-255 was converted (a) ( C H 2 O H ) 2 , PPTS, Q H * , reflux [82%] (b) L D A , THF, -78 °C; B r C H 2 C 0 2 M e , TBAI, -78 °C—>r.L 93%, based on recovered 262] (c) DIBAL, THF, 0 °C [85%] (d) NaH, T H F ; CH 3 I [90%] (e) 1 M HC1, MejCO [92%] (0 NaH, D M S O ; l-iodo-3-(r-butyldiphenylsUyloxy)pentane (270b) [65%] (g) NaH, D M S O ; CH 3 I [80%] (h) T B A F , T H F [90%] (i) C r Q 3 , aq. H 2 S 0 4 , M e 2 C O , 0 °C [87%] 0) p-TsOH, C 6 H6, reflux [84%]. Scheme 3.9. Preparation of Tricyclic Enone (257) from (-)-Enone-ester ent-255. [N.B. R = TBDPS] to the bicyclic ketal-ester 262 (Scheme 3.9) through treatment with ethylene glycol, pyridinium p-toluenesulfonate (PPTS) in refluxing benzene.92b'c The use of p-toluenesulfonic acid as an 75 alternative acid catalyst923 in this reaction resulted in gradual decomposition of enone-ester ent-255 to a dark-brown tar from which only low yields of ketal-ester 262 could be isolated. As expected, the infrared spectrum of ketal-ester 262 showed only a single ester carbonyl absorption, at 1742 cm- 1 . Other spectroscopic data ^ H NMR, low and high resolution mass spectra) supported the identification of the reaction product as being the ketal-ester 262. Subsequently, a-alkylation of the methyl ester was attempted. Treatment of a solution of lithium diisopropylamide and ketal-ester 262 in THF with methyl bromoacetate resulted in only -50% conversion of starting material to the desired product. Adjustment of reaction times and reactant concentrations did not improve the efficiency of the reaction. However, upon addition of dry tetrabutylammonium iodide or lithium iodide (0.3-0.5 eq. ) 1 3 3 to the reaction mixture, complete conversion of starting material to product (>90% yield) was achieved. The ketal-diester 263 was obtained as a single diastereomer, as ascertained by 400 MHz lU NMR spectroscopy, T L C , and GLC. The diastereoselectivity of the alkylation reaction with methyl bromoacetate can be explained using a rationale94 analogous to that presented in the previous chapter of this thesis (cf. Scheme 2.15, p. 44). Actually, the exact configuration at C(20) is of no concern to us because we realize that at a later stage in the synthetic plan, this particular carbon will become sp^ hybridized. In any case, we assumed that the C(20) configuration of our product was that predicted by our model, and shown in structure 263. The infrared spectrum of ketal-diester 263 exhibited a carbonyl stretching band at 1741 c m - 1 . The 400 MHz J H NMR spectrum of 263 exhibited, most notably, the presence of two singlets at 3.64 and 3.68 ppm that represent the protons of the two methyl ester (methoxycarbonyl) groups. The integrity of the ketal protective group is apparent because of the four-proton multiplet at 3.84—4.00 ppm, while the vinyl proton H(15) is represented by a broad singlet at 5.27 ppm. The 75 MHz 1 3 C NMR spectrum is likewise consistent with that expected for ketal-diester 263. The two signals at 172.4 and 175.4 ppm can be assigned to the two carbonyl carbons (C(21) and C(23)) of ketal-diester 263. 76 Having established the identity of ketal-diester 263 it was decided that the ester functional groups should be protected to permit the eventual construction of the tetracyclic limonoid skeleton. Thus, reduction of the ketal-diester 263 using either lithium aluminum hydride or diisobutylaluminum hydride in THF yielded ketal-diol 264. Although the yields of the products obtained using either reagent were comparable, the work-up of the reaction involving lithium aluminum hydride was cumbersome on account of the viscous and gelatinous nature of the aqueous phase. The infrared spectrum of ketal-diol 264 exhibited a broad absorption at 3340 c m - 1 that corresponds to an O - H stretching vibration. Subsequent treatment of ketal-diol 264 with sodium hydride (2.2-2.5 eq) followed by methyl iodide (2.2-2.5 eq) yielded dimethoxy-ketal 265 after 8 h. The progress of the reaction could be followed conveniently by T L C . It was observed that if the reaction mixture was analyzed by T L C prior to the reaction reaching completion, an additional product, whose Rf in 50% acetone-pet. ether (0.49) was intermediate between that of the starting ketal-diol 264 (0.28) and dimethoxy-ketal 265 (0.67). The identity of this new intermediate was not determined, but is assumed to be the hydroxy-methoxy-ketal 266 (Equation 3.1). It is possible that because the C(21)-hydroxyl group in 264 is closer to the tertiary C(20) carbon than the C(23) hydroxyl group, the C(21)-hydroxyl group is more hindered than that at C(23), and hence, undergoes methylation less readily than the C(23) hydroxyl group. •1) Finally, hydrolysis of the ketal 1 0 2 in dimethoxy-ketal 265 yielded dimethoxy-enone 267 in which provision has been made for the later construction of the furanoid side-chain unit that is a structural feature of most tetracyclic limonoids. The presence of an enone functional group was supported by an infrared band at 1660 cm- 1 (C=0 stretch). The 400 MHz lU NMR spec-77 trum of 267 exhibited a broad singlet at 5.71 ppm, which is assigned to vinyl proton H(8). The chemical shift of the H(8) signal is consistent with that expected for a-vinyl protons of a,/J-unsaturated ketone systems. Proton signals for the two methoxy groups occur at 3.27 and 3.31 ppm. ii. Preparation of Tricyclic Enone 257 from Bicyclic Enone 267. With the dimethoxy-enone 267 in hand we were ready to undertake construction of the B-ring and introduce the C(8) methyl group that is present in many of the the limonoids, including azadiradione (215). Retrosynthetic analysis (Scheme 3.10) suggested that the tricyclic enone 257 could be constructed through intramolecular aldol condensation of the diketone 268. Diketone 268 could, in turn, be obtained from hydroxy-ketone 269, and 269 can be derived from dimethoxy-enone 267 through successive alkylation of 267 with a suitably functionalized five-carbon alkyl halide and methyl iodide. Scheme 3.10. Retrosynthetic Analysis of Tricyclic Dienone 257. Structural considerations suggested that a possible five-carbon alkylating agent could be l-iodo-3-silyloxypentane (270; Scheme 3.11). In work related to the preparation of Wieland-Miescher ketone analogues, Mander and co-workers employed l-iodo-3,3-ethylenedioxypentane (271)134 and l-iodo-3-(trimethylsilyloxy)pentane (270a)134 as alkylating agents. In our hands, the preparation of ketal-iodide 271 from commercially available l-chloro-3-pentanone (272) was only marginally successful. Although l-chloro-3-pentanone (272) could be converted to the corresponding iodide 273, reaction of iodide 273 with ethylene glycol or 2,2-78 ethylenedioxybutane135 and p-toluenesulfonic acid in refluxing benzene yielded a mixture of products from which only a small amount of the desired ketal-iodide 271 could be separated inconveniently through repeated distillation under reduced (~0.1 mm Hg) pressure. Reversing the order of the iodination and ketalization steps was equally unsatisfactory. Accordingly, we turned our attention to the synthesis of the alternative l-iodo-3-(f-butyldiphenylsilyloxy)pentane 270b (Scheme 3.11). Our synthesis of l-iodo-3-(f-butyldiphenyl-silyloxy)pentane (270b) was based on Mander's procedure 1 3 4 for the preparation of the trimethylsilyloxy analogue 270a (in order to improve the hydrolytic stability of our alkylating agent, however, we chose instead to replace the trimethylsilyl protective group in 270a with the more robust f-butyldiphenylsilyl group). Thus, commercially available l-chloro-3-pentanone (272) was reduced using sodium borohydride in methanol to yield racemic l-chloro-3-pentanol (274). Protection of the hydroxyl group of 274 with r-butyldiphenylsilyl chloride and imidazole in D M F 9 3 yielded silyloxy-chloride 275b. Finally, conversion of the chloride 275b to iodide 270b was accomplished through a Finkelstein reaction (Nal, acetone, reflux). 1 3 6 d,c O H OR OR 274 275a (R = SiMe 3) 270a (R = SiMe 3) 275b (R = TBDPS) 270b (R = TBDPS) (a) NaBH4, MeOH, 0 °C [95%] (b) Me 3 SiCl or TBDPS-C1, imidazole, D M F [98%] (c) Nal, acetone, reflux [77%] 271 (d)(CH2OH)2,/>-TsOH or P P T S . Q H ^ reflux. Scheme 3.11. Preparation of l-Iodo-3-(r-butyldiphenylsilyloxy)pentane (270b). Many examples illustrating the a-alkylation of enones 1 3 5- 1 3 7 have been documented in the literature. The use of sodium hydride in dry dimethyl sulfoxide1 3 8 as a reliable method for the chemoselective formation of the thermodynamic dienolate of a,/J-unsaturated ketones has been documented amply in the literature. Addition of sodium hydride to dimethyl sulfoxide that had been distilled from calcium hydride resulted in proton transfer to form the 79 methylsulfinylmethyl, or 'dimsyl' 1 3 8 anion. Subsequent addition of an enone, such as dirnethoxy-enone 267, resulted in formation of the thermodynamic dienolate 276 (Equation 3.2). TBDPSO [R = 3-(f-butyldiphenylsilyloxy)pent-l-yl] Addition of racemic silyloxy-iodide 270b to the reaction gave a mixture of products. The desired a-alkylated enone 277 was obtained as a mixture of diastereomers [TLC R/ (60% EtOAc-pet. ether): 0.28 and 0.31] that were not separated. The combined yield of the two diastereomers 277 was 65%. In addition, a considerably less polar compound [TLC R/ (60% EtOAc-pet. ether): 0.86] was isolated in ~28% yield. Unfortunately, this latter by-product could not be purified sufficiently to allow detailed characterization. Instead, based on literature precedent,1370 the by-product was assumed to be the dienol ether 278, formed as a result of O-alkylation of the thermodynamic dienolate 276 with silyloxy-iodide 270b. That subsequent reaction of the supposed dienol ether 278 with 1 M HC1 resulted in near-quantitative recovery of dimethoxy-enone 267 supports the proposal that the by-product was likely the dienol ether 278. The spectral characteristics of the recovered enone 267 were identical in all respects to that of the enone sample that was used for the alkylation reaction. The infrared spectrum of alkylated enone 277 exhibited a carbonyl stretching absorption at 1653 c m - 1 . Although the observed absorption occurs below the range normally expected for a,/3-un saturated carbonyl groups,1 0 1 it is pertinent to note that in a structurally similar bicyclic a-alkylated a,/3-unsaturated ketone 1 3 5 a carbonyl absorption occurred at 1655 c m - 1 . The 400 MHz *H NMR spectrum provided further evidence in support of the identity of alkylated enone 277. Although the spectrum of 277 indicated that enone 277 was present as a 50:50 mixture of 80 diastereomers, it was still possible to correlate parts of the spectrum to the structure of 277. For example, the combined signals at 7.60-7.72 (m, 4H), 7.30-7.42 (m, 6H) and 1.04 (s, 9H) all supported the presence of a f-butyldiphenylsilyl protective group in the molecule. The three-proton triplet at 0.77 ppm could be assigned to the terminal methyl group of the newly added alkyl chain while the three-proton singlet at 0.99 ppm could be assigned to the protons of the C(13)-methyl group. With regards to the regiochemistry of the alkylation reaction, the absence of signals between 4.5-6.0 ppm of the spectrum indicates there are no vinyl protons present in enone 277, and supports the presumption that alkylation at C(8) of dienolate 276 has occurred. Had alkylation at C(l 1) occurred instead, a vinyl proton would still be present at C(8) and would have given rise to a signal between 4.5-6.0 ppm. 1 0 1 At this point, a second, similar alkylation of enone 277 with methyl iodide yielded the /3,y-unsaturated enone 279 (cf. Equation 3.3). Thus, treatment of the epimeric enones 277 with methylsulfinylmethylsodium ('dimsylsodium'),138 prepared in situ by reaction of sodium hydride with dry dimethyl sulfoxide, yielded dienolate 280. It was expected that due to steric considerations, alkylation with methyl iodide would occur from the face of the enolate opposite the C(13) methyl group. The progress of the alkylation reaction was monitored by T L C , and after the starting material (277) had been consumed totally, the desired unsaturated enone 279 was obtained as a 1:1 mixture of C(5) diastereomers. A minor by-product (cf. 281, Equation 3.3) arising from the <9-alkylation of dienolate 280 with methyl iodide was also isolated. [R = 3-(f-butyldiphenylsilyloxy)pent-l-yl] TBDPSO 81 The 400 MHz *H NMR spectrum of the product (279) showed considerable doubling and overlap of signals due to the presence of diastereomeric compounds. Regardless, it is possible to discern two pairs of three-proton singlets at 0.90 and 0.92 ppm, and 0.99 and 1.06 ppm that could be assigned to the C(13)-methyl groups and the newly introduced C(8)-methyl groups of the two diastereomeric ketones 279. In addition, the doublets of doublets at 5.26 and 5.31 ppm can be assigned to the C(15) vinyl protons for the diastereomeric ketones 279 and provide evidence that alkylation had occurred at C(8) and that the double bond that had previously occupied the C(8)-C(14) positions is now found between C(14) and C(15), as expected. Indeed, the carbonyl absorption of ketones 279 now falls at 1708 c m - 1 which is in the range expected for non-conjugated carbonyl groups. Unfortunately, due to the complexity of the *H NMR spectrum, which exhibited many overlapping signals arising from the two epimeric products, it was not possible at this point to perform an NOE experiment to determine the configuration at C(8). Accordingly it was decided to postpone stereochemical determination to a later stage of the project. Cleavage of the silyl protective group9 3 in 279 occurred without incident. Treatment of enone 279 with tetrabutylammonium fluoride (2 eq) in THF yielded the epimeric hydroxy-enones 269 (VO_H = 3456 c m - 1 ; vc=o = 1709 cm - 1 ) , which were not purified further but submitted directly to Jones oxidation conditions [Cr03, aqueous H2SO4, acetone]139 to afford diketone 268 in 87% yield. As expected, the infrared absorption at 3456 c m - 1 is no longer present in the spectrum of diketone 268. A peak at 1713 c m - 1 , however, does support the presence of carbonyl groups in the molecule. With the loss of the stereocenter at C(5) the 400 MHz *H NMR spectrum is simplified greatly. For example, the *H NMR spectrum supports the presence of three methyl groups in 268, as evidenced by signals at 0.99 (t, 3H; C(10)-methyl group), 1.01 (s, 3H; C(13)-methyl group), and 1.16 (s, 3H; C(8)-methyl group) ppm. The doublet of doublets at 5.46 ppm represents the C(15)-vinyl proton while the two singlets at 3.27 and 3.31 ppm can be assigned to the protons of the two methoxy groups. 82 Finally, diketone 268 was allowed to undergo acid-catalyzed intramolecular aldol condensation [p-TsOH, C6H6> reflux] 1 0 9 to afford the tricyclic enone 257 in 84% yield. The infrared spectrum of tricyclic enone 257 exhibited a carbonyl stretching vibration at 1662 c m - 1 and also, absorptions at 1625 and 1602 c m - 1 representing the C=C absorptions. In the 400 MHz NMR spectrum, the three-proton doublet at 1.75 ppm can be assigned to the C(10)-methyl group, and is within the range expected for a methyl group that is adjacent to a vinyl group. The two singlets at 3.29 and 3.32 ppm can be assigned to the methoxy protons while the singlets at 0.82 and 1.31 ppm can be assigned to the C(13)-methyl and C(8)-methyl protons, respectively. Irradiation of the signal at 0.82 ppm resulted in enhancement of the multiplet at 1.69-1.87 ppm, but not the doublet at 1.75 ppm (cf. Table 5.18, p. 187). Through the aid of a COSY spectrum (cf. Table 5.19, p. 188), this multiplet was assigned to H(22), H(20), and H(12). Furthermore, enhancements of the two singlets at 3.32 and 3.29 ppm [-OMe, -OMe] and the signal at 3.30-3.38 [H(21)] were observed. These results suggest that it would be reasonable to assign the signal at 0.82 ppm to the C(13)-methyl protons. By elimination, the singlet at 1.31 ppm is assigned to the C(8)-methyl protons. We now sought to establish the stereochemistry of the C(8)-methyl group using data gained from NOE experiments (cf. Table 5.18, p. 187). Irradiation of the C(13)-methyl signal did not result in enhancement of the intensity of the C(8)-methyl signal. Back-irradiation of the C(8)-methyl signal resulted in enhancement of not the C(13)-methyl signal, but instead, the H(15) vinyl proton signal, among others. Similarly, irradiation of the H(15) vinyl signal (5.41-5.48 ppm) resulted in enhancement of the C(8)-methyl signal, among others. Examination of molecular models of enone 257 and its C(8) epimer suggested that the presence of an NOE between the C(8)-methyl group and H(15) would be more likely if the C(8)-methyl group adopted a /3-orientation, that is, and to the C(13)-methyl group. Thus, we feel confident that the correct structure for our tricyclic enone product is that represented by structure 257. 83 iii. Future Directions Because of time and material constraints it was decided not to undertake further synthetic studies on tricyclic enone 257 at this time. Thus, in summary, the tricyclic enone 257, a potential BCD-ring intermediate for the enantiospecific synthesis of limonoids, has been prepared140 in azadiradione (215) 284 Scheme 3.12. Projected Completion of the Limonoid Synthesis. ten steps from bicyclic enone-ester ent-255 which was derived from (-)-camphor (ent-9). It is proposed (Scheme 3.12) that further C(10)-alkylation of dienone 257 followed by cyclization (cf. Robinson annulation) would yield dienone 282. Subsequent C(4)-methylation of tetracyclic dienone 282 should provide dienone 283, an intermediate in which provision has been made for 84 the introduction of a furanoid unit at C(17) as well as oxygen functionality at C(7) and C(16), to yield acetoxy-diketone 284 and thence, azadiradione (215). 85 Chapter 4 Further Studies on the Chemistry of 4-Methylcamphor: A Multiple Rearrangement Process in the Bromination of ewd0-3-Bromo-4-methylcamphor 86 4. Further Studies on the Chemistry of 4-Methylcamphor: A Multiple Rearrangement Process in the Bromination of en^0-3-Bromo-4-methylcamphor (a) Introduction Our ongoing interest in triterpenoid and steroid synthesis led us to consider as potential targets the euphane (e.g. euphol (204; Scheme 4.1)) and tirucallane (e.g. tirucallol (205)) triterpenoids, both of which have the (13a,14/J) absolute configuration as drawn, as well as the lanostane (e.g. lanosterol (285)) triterpenoids and 14a-methyl steroids (e.g. 14a-methylandrostenedione (286) and 14a-methylestrone (287)), both of which have the opposite, (13/?,14a) absolute configuration as drawn. Despite the biosynthetic importance of many of these compounds, few total syntheses of representative members of these classes of compounds have been reported. euphol (204; = H ; R 2 = C H 3 ) tirucallol (205; Rx = C H 3 ; R 2 = H) O lanosterol (285) O ^ H O ' 14a-methyIandrost-4-en-3,17-dione (286) 14a-methylestrone (287) Scheme 4.1. Structures of Representative 14-Methyltriterpenoids and 14-Methyl Steroids. (b) Previous Synthetic Routes to Euphanes, Tirucallanes, Lanostanes, and 14-Methyl Steroids The first successful total synthesis of a euphane or tirucallane triterpenoid141 was not published until 1990, when the late W.S. Johnson and his co-workers at Stanford reported a total 87 synthesis of euphol (204) and tirucallol (205) that was based on a biomimetic polyolefin cyclization strategy (Scheme 4.2). Dienediynol 288 was prepared from 2,3-dimethyl-l,3-butadiene (289) in eight steps. Treatment of 288 with 5:1 formic acid-pentane at 0 °C followed by methanolysis of the resulting enol formate yielded tetracyclic ketone 290 in 89% yield. Reduction of the C(20) keto group (triterpenoid numbering) followed by A-ring expansion via tandem ozonolysis-aldol condensation yielded hydroxy-enone 291. Conventional reactions were used to convert 291 to enedione 292. Enedione 292 was converted to a mixture of C(20)-epimeric hydroxy-acetals 293 and 294 that were separable by chromatography. Hydroxy-acetal 293 was converted to (±)-euphol (204) in three steps while hydroxy-acetal 294 was converted to (±)-tirucallol (205), also in three steps. euphol (204; Rj = H ; R 2 = C H 3 ) 293 (Rj = H ; R 2 = C H 3 ) 292 tirucallol (205; Rx = C H 3 ; R 2 = H) 294 (Rj = C H 3 ; R 2 = H) Scheme 4.2. Johnson et ai: Total Synthesis of (±)-Euphol (204) and (±)-Tirucallol (205). Five years before Johnson and co-workers reported their synthesis of euphol (204) and tirucallol (205), Kolaczkowski and Reusch documented their attempt to synthesize a euphane triterpenoid.142 Although they were not successful in achieving their goal, they did succeed in completing a total synthesis of a compound (295) possessing the 5-e/?/-euphane ring system. A 88 summary of the synthesis is presented in Scheme 4.3. Racemic Wieland-Miescher ketone (119) was converted in two steps to the hydrindandione 296 in which the relative configuration of the two angular methyl groups is and, as required for the euphane skeleton. Transformation of 296 to the dienone 297 set the stage for a Lewis acid catalyzed Diels-Alder reaction with 2-methoxy-5-methyl-l,4-benzoquinone (298) to yielded the tetracyclic trione 299. Unfortunately at this stage of the synthesis, all attempts by Kolaczkowski and Reusch to epimerize the C(5) stereocenter were unsuccessful. Carrying on, however, enol acetate formation followed by photoepimerization provided dione 300. Conventional reactions were used to convert 300 to the hydroxy-diketone 295, which bears the 5-epi'-euphane carbon skeleton.142 O Scheme 4.3. Kolaczkowski and Reusch: Synthesis of the (±)-5-epi-Euphane Ring System.1 4 2 As for the lanostane triterpenoids, the first synthesis of lanosterol (285), from cholesterol (301), was reported in 1957 by Woodward, Barton, and their respective co-workers (Scheme 4.4). 1 4 3 However, Woodward and co-workers had previously completed a 37-step total synthesis of cholesterol (301)144 following a synthetic plan that was based on a C D * (302) - ¥ B C D * (303) -> A B C D * (304) -> ABCD (305) strategy; the notation D * - » D represents the 89 contraction of a six-membered ring (D*) to the required five-membered D-ring. Thus, the synthesis of lanosterol (285) from cholesterol (301) represents also the first total synthesis of this important natural product.143 24,25-dihydrolanosterol cholesterol (301) (lanostenol; 306) lanosterol (285) Scheme 4.4. Woodward, Barton, et al: Total Synthesis of (±)-Lanosterol (285).14:1 During the course of studies on polyolefin cyclizations by van Tamelen and Anderson, a synthesis of 24,25-dihydrolanosterol (lanostenol; 306) from (5)-(-)-limonene (307) was developed (Scheme 4.5). 1 4 5 (S)-(-)-Limonene (307) was first converted to the cyclopentenol derivative 308, which would eventually become the D-ring of the target molecule. Nucleophilic substitution of the bromo group in ketal-bromide 309, prepared from farnesol (228), with the ylide 310 derived from 308 followed by functional group manipulations yielded epoxy-triene 90 312. Treatment of epoxy-triene 312 with tin(IV) chloride yielded a mixture of four isomeric tetracyclic alcohols from which 24,25-dihydroparkeol (313) was isolated as a minor (3.5%) product. Acid-catalyzed isomerization of the A 9 - 1 1 double bond in 313 to the A 8 - 9 position furnished 24,25-dihydrolanosterol (lanostenol; 306), which was also an intermediate in the total 311 312 24,25-dihydroparkeol (313) lanosterol 24,25-dihydrolanosterol (285) (lanostenol; 306) Scheme 4.5. van Tamelen and Anderson: Formal, Enantiospecific Synthesis of Lanosterol.145 synthesis of lanosterol by Woodward, Barton, and their respective co-workers.1 4 3 As well, in view of the fact that both enantiomers of the monoterpenoid limonene are readily available,13 the preparation of 24,25-dihydrolanosterol (306) by van Tamelen and Anderson 1 4 5 therefore constitutes a formal, enantiospecific synthesis of lanosterol (285). 91 Recently, a considerably more concise, formal, convergent synthesis of (±)-lanosterol (285) was reported by Corey and co-workers (Scheme 4.6).1 4 6 Initially the Grundmann ketone (314) was converted to the bicyclic vinyl iodide 315. Concurrently, (5)-6,7-oxidogeraniol (316) Grundmann ketone (314) 315 (X = I) ^ 318 (X = Li) 24,25-dihydrolanosterol (lanostenol; 306) cf. Woodward, Barton, \ et al. (Scheme 4.3) lanosterol (285) Scheme 4.6. Corey et al.: Formal, Enantiospecific Synthesis of Lanosterol.146 was converted to epoxy-aldehyde 317. Addition of the vinyllithium compound 318, derived from iodide 315, to an ethereal solution of epoxy-aldehyde 317 in the presence of magnesium bromide furnished a 1:1 mixture of diastereomeric epoxy-alcohols from which the la epimer 319 (steroid/triterpenoid numbering system) could be separated by chromatography. Conversion of the 7a-hydroxyl group to a silyl group permitted the execution of a Lewis acid promoted polyolefin cyclization followed by acetylation to yield the tetracyclic acetate 320, and in three 92 further steps, 24,25-dihydrolanosterol (lanostenol; 306). 1 4 3 The successful preparation of 306 completes a formal, enantiospecific synthesis146 of the triterpenoid (+)-lanosterol (285). The synthesis of 14a-methyl steroids has been an ongoing theme in the research program of Bull and co-workers in South Africa. A representative 14a-methyl steroid is the 14a-methylestrone derivative 321, whose total synthesis was reported by Bull and Bischofberger in 1983 (Scheme 4.7).147 The synthesis starts with the Reusch diketone 296 (cf. Scheme 4.3).142 Elaboration of 296 to the enedione 322 followed by conjugate addition of m-methoxybenzylmagnesium chloride in the presence of copper(II) acetate yielded diketone 323. Acid-catalyzed ring closure followed by dehydration and ketalization yielded a 1:1 mixture of isomeric tetracyclic ketals 324a and 324b. Treatment of the A 9 ' 1 1 unsaturated compound 324a with lithium in liquid ammonia followed by aqueous trifluoroacetic acid yielded the 14a-methylestrone derivative (321).147 Interestingly, the bioactivity of 14a-methyl steroids have (321) 324b A' Scheme 4.7. Bull and Bischofberger: Total Synthesis of a 14a-Methyl Steroid, (±)-3-methoxy-14-methyl-14a-estra-l,3,5(10)-trien-17-one(321).147 not, to our knowledge, been examined. It is conceivable, however, that because of their structural similarity to natural steroids, 14a-methyl steroids, in general, could have potential clinical applications. Development of reliable synthetic routes to 14a-methyl steroids would 93 lead to the increased availability of these compounds and in turn, could stimulate further studies on their biochemical and pharmacological properties. (c) The Use of 4-Methylcamphor in Triterpenoid and Steroid Synthesis In devising our strategy for the synthesis of members of the euphane, tirucallane, lanostane, and 14a-methyl steroid families, we chose to draw on experience gained previously from our own research program. In 1987, Hutchinson and Money published an enantiospecific synthesis of estrone (326)40 in which (+)-camphor (9) was converted to the bicyclic C,D enone 325 en route to (-)-estrone (e«f-estrone; ent-326; Scheme 4.8). By analogy, we envisioned that each of euphol (204) and tirucallol (205) could be derived from an analogous bicyclic enone ent-328 in which there is present an extra methyl group at C(14) (triterpenoid/steroid numbering) and to the C(13)-methyl group. Recognizing that enone 325 was derived from camphor (9), we reasoned that because the C(14) position in the triterpenoid (or steroid) C,D ring system corresponds to C(4) in the original camphor (or bornane) system, it should be possible to synthe-size the 13,14-anf/-dimethyl-enone 328 or its enantiomer if only we employed the appropriate enantiomer of 4-methylcamphor (87) as starting material instead. Indeed, an efficient route to 4-methylcamphor (87) from camphor (9) has been devised previously by our group (cf. Scheme 1.21).72 Although our original route provided material that was only ~60% enantiopure, we have recently reported an alternative enantiospecific synthesis of ~100% enantiopure 4-methylcamphor (87).73 94 In the above-mentioned synthesis of estrone (326) by Hutchinson and Money (cf. Scheme 4.8) 4 0 camphor (9) was brominated successively to provide endo-3-bromocamphor (20), e«rfo-3,9-dibromocamphor (22), and thence enrfo-3,9,10-tribromocamphor (32). Subsequent chemoselective debromination of 32 with zinc in 1:1 acetic acid-diethyl ether yielded 9,10-dibromocamphor (33), and base-promoted ring cleavage of 9,10-dibromocamphor (33) yielded a cyclopentanoid hydroxy-acid 37 that could be elaborated to the bicyclic C,D enone intermediate 325 in three further steps. By analogy (cf. Scheme 4.8), we thought it would be reasonable to brominate 4-methylcamphor (87) successively to yield e«do-3-bromo-4-methylcamphor (327), endo-3,9-dibromo-4-methylcamphor (328), e«rfo-3,9,10-tribromo-4-methylcamphor (329), and thence 9,10-dibromo-4-methylcamphor (330). Subsequent base-promoted ring cleavage of 9,10-dibromo-4-methylcamphor (330) would be expected to provide hydroxy-acid 331 which would be used in turn to prepare the C,D enone 328. The enantiomeric C,D enone ent-328 would, of course, be derived from the enantiomeric 4-methylcamphor (ent-ST). However, upon execution of this synthetic plan, it was soon observed that the bromination of e«do-3-bromo-4-methylcamphor (327) proceeded abnormally. The product of the bromination was determined to be a tribrominated camphor derivative, and not e/zc?o-3,9-dibromo-4-methylcamphor (328) as expected. On the basis of spectroscopic data available at the time, it was assumed that the identity of this product was en<io-3,9,10-tribromo-4-methylcamphor (329). Proceeding further, chemoselective debromination of 329 to yield "9,10-dibromo-4-methylcamphor" (330) occurred uneventfully, but in the following step, all attempts to effect base-promoted ring cleavage of 330 failed. After considering the implications of these unexpected results it was subsequently proposed that the bromination had not yielded endo-3,9,10-tribromo-4-methylcamphor (329) as 95 Synthesis of Estrone ,10 40 (+)-camphor (9) r — 20 (X = Br; Y = H ; Z = H) p ^ : 22 (X = Br; Y = Br; Z = H) Z !T 32 (X = Br; Y = Br; Z = Br) 33 (X = H ; Y = Br; Z = Br) - 1 325 enf-estrone (ent-326) Proposed Approach to the Euphanes and Tirucallanes 9 Y H 0 Cf< 1 0 - C r < z 3 / ^ y (+)-4-methyl-campbor (enf-87) x • - - ent-321(X = Br; Y = H ; Z = H) '. e/if-328 (X = Br; Y = Br; Z = H) ent-329 (X = Br; Y = Br; Z = Br) ent-330 (X = H ; Y = Br; Z = Br)- 1 C02H e/tf-331 enr-328 euphanes tirucallanes Proposed Approach to the Lanostanes and 14of-Methvl Steroids (-)-4-methyl- , - - - 327 (X = Br; Y = H ; Z = H) camphor |^T. 328 (X = Br; Y = Br; Z = H) (87) ^ 329 (X = Br; Y = Br; Z = Br) *-*" 330 (X = H ; Y = Br; Z = Br) -H02C 331 328 lanostanes 14a-methyl steroids Scheme 4.8. Comparison of the Proposed Routes to the Euphanes, Tirucallanes, Lanostanes, and 14o>Methyl Steroids to the Hutchinson-Money Synthesis of Estrone.40 96 9 9 332 ent-332 expected, but possibly, the isomeric endo-3,9-dibromo-4-(bromomethyl)camphor (332).1 4 8 A detailed review of these observations, as well as the evaluation of a proposed mechanism for the "anomalous" bromination of e«rfo-3-bromocamphor (327) to yield 332 will constitute the remainder of this chapter. (d) Results and Discussion /. Preparation of 4-Methylcamphor (87), tndo-3-Bromo-4-methylcamphor (327), and endo-5,9-Dibromo-4-(bromomethyl)camphor (332). The first stage of the project involved the preparation of 4-methylcamphor (87; cf. Schemes 1.22 and 4.9).72 To this end, enantiopure (+)-camphor (9) was treated with the ylide generated in situ from reaction of methyltriphenylphosphonium bromide and n-butyllithium in THF to provide 2-methylenebornane (88). Treatment of 2-methylenebornane (88) with a cata-(+)-camphor (-)-2-methylene (+)-4-methylisobornyl (+)-4-methyl- (-)-4-methyl-(9) bornane(88) acetate (89) isoborneol (90) camphor (87) (i) C H 3 P P h 3 + B r " , BuLi, THF, reflux [87%] (ii) H 2 S 0 4 , HOAc [73%] (iii) L i A l H 4 , T H F , 0 °C; H 2 0 [99%] (iv) C r Q 3 , aq. H 2 S 0 4 , acetone, 0 °C [99%]. Scheme 4.9. Money et al.: Preparation of (-)-4-Methylcamphor (87) from (-f)-Camphor. lytic amount of concentrated sulfuric acid in acetic acid resulted in acid-catalyzed rearrangement of the bornane skeleton followed by capture of acetic acid and proton loss to yield 4-methylisobornyl acetate (89). Reduction of acetate 89 with lithium aluminum hydride afforded 4-methylisoborneol (90), and subsequent Jones oxidation provided 4-methylcamphor (87). 97 Despite that enantiopure (+)-camphor (9) was used as starting material, the product that was obtained, 4-methylcamphor (87), was found to be only 60% enantiopure. Although the specific rotation of the 4-methylcamphor (87) so obtained was in agreement with those quoted previously by others,233 a 400 MHz lU NMR spectrum of the same sample of 87 recorded in the presence of a chiral shift reagent, Eu(hfc)3, showed clearly two sets of signals arising from the two enantiomers of 4-methylcamphor (87).72 Comparison of appropriate *H NMR integral values revealed that the enantiomers were present in a ~4:1 ratio (~60% e.e.). That the 4-methylcamphor (87) obtained through our synthetic route (Scheme 4.9) exhibited a specific rotation that was in agreement with those reported elsewhere233 in the literature despite being an unequal mixture of enantiomers suggests that none of the literature routes to 4-methylcamphor (87) published before 1990 yields enantiopure products. W M = Wagner-Meerwein rearrangement 3,2-exo-Me = 3,2-exo-methyl shift 6,2-H = 6,2-hydride shift Scheme 4.10. Mechanism for the Transformation of (-)-2-Methylenebornane (88) to (+)-4-Methylisobornyl Acetate (89) (60% e.e.).65'12 The loss of enantiopurity in the product can be explained by the mechanism outlined in Scheme 4.10. Initial protonation of 2-methylenebornane (88) and Wagner-Meerwein rearrangement yields a tertiary carbocation 333 that then undergoes a 3,2-exo-methyl shift to 98 yield a new carbocation 334. A further Wagner-Meerwein rearrangement of 334 gives rise to 335, which can react with acetic acid to afford 4-methylisobornyl acetate (89) after proton loss. Alternatively, carbocation 335 can undergo a competing 6,2-hydride shift to yield the enantiomeric carbocation ent-335, which can also be intercepted by acetic acid to yield the enantiomeric 4-methylisobornyl acetate (ent-89). If the rate at which the 6,2-hydride shift occurs in 335 is faster than that at which 335 is captured by acetic acid then it would be possible to obtain an unequal product mixture of enantiomeric 4-methylisobornyl acetates 89 and ent-89. The validity of this mechanistic proposal has been evaluated through experiments65'72 involving the use of deuterium-labelled substrates.149 In one experiment (Equation 4.1), treatment of 2-dideuteriomethylenebornane (336) with deuterioacetic acid (CH3CQ2D) and sulfuric acid (H2SO4) led to the formation of 4-trideuteriomethylisobornyl acetate (337), presumably as an unequal mixture of enantiomers as described previously. That 4-(trideuteriomethyl)isobornyl acetate (337) was obtained as product 6 5 ' 7 2 is consistent with the proposed reaction pathway (cf. Scheme 4.10), which predicts that the exocyclic methylene group in 2-methylenebornane (88) becomes the C(4)-methyl group in 4-methylisobomyl acetate (89). In another experiment (Equation 4.2), 6 5' 7 2 8-deuterio-2-methylenebornane (338) was subjected to acid-catalyzed rearrangement conditions (HOAc, H2SO4) to yield a 4:1 mixture of 8-deuterio-4-methylisobornyl acetate (339) and 9-deuterio-4-methylisobornyl acetate (340), respectively. It is interesting to note that the structures of 339 and 340 belong to opposite enantiomeric series. This result provides support for the proposal that the carbocation 335 (Scheme 4.10) can give rise to both of the enantiomeric acetates 89 and ent-89. 2-dideuterio-methylenebornane (336) 337 ent-337 99 HOAc, H 2 S 0 4 8-deuterio-2-methylenebornane (338) OAc AcO. (4.2) Recently, an alternative, analogous procedure (Scheme 4.11) has been developed in which enantiopure (+)-camphor (9) was converted to 4-methylcamphor (87) with no detectable loss of enantiopurity (NMR, G L C ) . 7 3 Unfortunately, the yield of one of the synthetic steps, namely the conversion of 4-methylisoborny] bromide (91) to the diastereomeric alcohols 90 and 92 remains unoptimized and low-yielding (~40%). Because the remainder of the chemistry in / (+)-camphor (9) (-)-2-methylene bornane (88) 4-methylisobornyl bromide (91) 90 (e;a?-2-hydroxy) 92 (endo-2-hydroxy) (-^-methyl-camphor (87) (i) C H 3 P P h 3 + B r _ , BuLi, THF, reflux [87%] (ii) 45% HBr, HOAc [87%] (iii) Mg, E t 2 0 ; 0 2 ; H 3 0 [40%] (iv) C r 0 3 , aq. H 2 S 0 4 , acetone, 0 °C [97%]. Scheme 4.11. Money and Palme: Preparation of Enantiopure (-)-4-Methylcamphor (87) from (+)-Camphor. 73 this project does not involve the use of chiral reagents it was deemed sufficient to use the enantiomerically impure material obtained through our original route (Scheme 4.9). In the next stage of the project, 4-methylcamphor (87) was converted (Scheme 4.12) to £rtcfo-3-bromo-4-methylcarnphor (327)72 by treatment with bromine in acetic acid at 80 °C. Subsequent reaction of 327 with bromine (2.2 eq) in chlorosulfonic acid yielded a tribromocamphor that was identified on the basis of spectroscopic data to be e7ido3,9-bromo-4-(bromomethyl)camphor (332).72 100 9 0 B r 2 , H O A c , 80 °C o B r 2 (2-2 eg), C1S03H Bt'"\£' O /J^f \96%1 " U^f 15 h [84%] Br B r ^ Br (-)-4-methyl- cm/o-3-bromo- entfo-3,9-dibromo-camphor (87) 4-methylcamphor (327) 4-(bromomethyl)camphor (332) Scheme 4.12. Bromination of 4-Methylcamphor (87) . 7 2 The structure of e/ido-3,9-dibromo-4-(bromomethyl)camphor (332) was verified primarily through its 400 MHz ! H NMR spectrum (Figure 4.1, p. 102). The signal at 4.92 ppm (d, J = 1.2 Hz, 1H) was assigned to the H(3eA:o) proton on the basis of its chemical shift. The COSY spectrum {cf. Table 5.21, p. 198) of enrfo-3,9-dibromo-4-(bromomethyl)camphor (332) showed a correlation betwen the H(3e ; c o) signal and that at 1.82 ppm, suggesting that the latter signal could be assigned to the C(5exo) proton. The group of four doublets between 3.4-4.1 ppm arise collectively from resonance of the C(9) and C(4') protons. The COSY spectrum suggests that the doublets at 4.06 and 3.52 ppm represent the diastereotopic protons of one of C(9) or C(4') while the doublets at 3.74 and 3.46 ppm represent the diastereotopic protons of the other, remaining carbon. Furthermore, a COSY correlation between the doublet at 3.74 ppm and the three-proton singlet at 1.24 ppm suggests that the two signals could be assigned to one of the diastereotopic C(9) protons and the C(8) protons, respectively. Presumably, this particular COSY correlation arises from the long-range (4J or W-) coupling of H(9) to H(8). Having assigned one of the H(9) protons facilitated assignment of the doublet at 3.52 ppm to the other H(9) proton. The doublets at 4.06 and 3.52 ppm represent the two diastereotopic H(4') protons. The singlet at 1.03 ppm can be assigned to H(10). By elimination, the remaining four signals between 1.45-2.25 ppm must represent the four protons associated with C(5) and C(6). The assignment of these signals to specific protons was performed recently with the aid of HETCOR (cf. Table 5.22, p. 198) and difference NOE experiments (cf. Table 5.20, p. 197). It has already been established that the signal at 1.82 ppm 101 arises from resonance of H(5ex0). The HETCOR spectrum shows that this proton signal and that at 2.19 ppm both correlate with the same 1 3 C signal. Thus, the signal at 2.19 ppm represents H(5end0). During the course of a difference NOE experiment, irradiation of the H(5end0) signal resulted in enhancement of the intensities of peaks at 4.06 and 3.52 (H(4')), 1.82 (H(5exo)), 1.52, and very weakly, at 1.70 ppm. Furthermore, irradiation of the C(10) methyl signal at 1.03 ppm resulted in intensity enhancements of signals at 1.70 ppm and 1.52 ppm, as well as the signals for H(8) and H(9) at 1.24 and 3.46 ppm, respectively. Irradiation of the H(9) proton signal at 3.74 ppm, on the other hand, caused enhancement of the geminal H(9) and H(5 e x o) signals [3.46 and 1.82 ppm, respectively] as well as that at 1.70 ppm. From the results of these three NOE experiments, it could be deduced that the signal at 1.70 ppm corresponded to the H(6ex0) proton and that at 1.52 ppm corresponded to the H(6en<j0) proton. Further difference NOE experiments were performed and the results of these experiments are summarized in Table 5.20 (p. 197). In summary, the NMR spectral data provide support for our revised proposal that bromination of £/ido-3-bromo-4-methylcamphor (327) had occurred at C(9) and C(4') rather than at C(10) as originally, anticipated. Finally, the structure of endo-3,9-dibromo-4-(bromomethyl)camphor (332) has been confirmed also by X-ray crystallographic analysis.1 5 0 ii. A Proposed Mechanism for the Bromination of tndo-3-Bromo-4-methylcamphor (327). A plausible mechanism for the remarkable transformation of endo-3-bromo-4-methylcamphor (327) to e/tJo-3,9-dibromo-4-(bromomethyl)camphor (332) is presented in Scheme 4.13. In the presence of two equivalents of bromine and chlorosulfonic acid, the carbonyl group of endo-3-bromo-4-methylcamphor (327) is protonated initially. Subsequent Wagner-Meerwein rearrangement leads to the tertiary carbocation 342 which undergoes a 103 Br 328 ( m i n o r by-product) 9 332 (major product) Scheme 4.13. Proposed Reaction Pathway for the Bromination of erafo-3-Bromo-4-Methyl-camphor (327). further 3,2-exo-methyl shift to yield carbocation 343. Carbocation 343 can lose a proton to generate the exocyclic alkene intermediate 344. Electrophilic bromination of the alkene 344 yields the dibromo-carbocation 345, which can either undergo a Wagner-Meerwein 104 rearrangement to provide carbocation 346 or a competing 3,2-exomethyl shift to provide carbocation 347. On the one hand, loss of a proton from 346 yields another exocyclic alkene 348 that can undergo a further electrophilic bromination step to yield tribromo-carbocation 349. Subsequent Wagner-Meerwein rearrangement of 349 followed by 3,2-exo-methyl shift and a further Wagner-Meerwein rearrangement yields, after proton loss, enrfo-3,9-dibromo-4-(bromomethyl)camphor (332) as the major product of the reaction. In the alternative pathway, carbocation 347 can undergo Wagner-Meerwein rearrangement and proton loss to yield ertdo-3,9-dibromo-4-methylcamphor (328) as a minor side-product. However, attempts to find reaction conditions that promoted exclusive formation of £fld<9-3,9-dibromo-4-methylcamphor (328) were unsuccessful. For example, when the reaction of e7zdo-3-bromo-4-methylcamphor (327) with bromine (2.2 eq.) in chlorosulfonic acid was stopped after 5 min, G L C analysis showed that the major components present in the product mixture (-1:1) were starting material (327) and e«do-3,9-dibromo-4-(bromomethyl)camphor (332); en<i<)-3,9-dibromo-4-methylcamphor (328) was present to only a small (<5%) extent. However, another experiment was carried out in which £«d<?-3-bromo-4-methylcamphor (327) was allowed to react with only one equivalent of bromine in chlorosulfonic acid. Under these reaction conditions, the starting material was totally consumed after 5 h, and it was possible to isolate a -1:1 mixture of ercdo-3,9-dibromo-4-methylcamphor (328) and e«c(o-3,9-dibromo-4-(bromomethyl)camphor (332; -61% combined yield). These two bromocamphor derivatives 328 and 332 could be separated easily. When purified 3,9-dibromo-4-methylcamphor (328) was treated with one further equivalent of bromine in chlorosulfonic acid, only one product was isolated. The isolated product was identified as endo-3,9-dibromo-4-(bromomethyl)camphor (332) and its spectroscopic characteristics ( 1H, 1 3 C NMR, and IR spectra) were identical to those obtained for a sample of g/zrfo-3,9-dibromo-4-(bromomethyl)camphor (332) obtained through the conventional route, that is, from end<>3-bromo-4-methylcamphor (327). 105 These observations seem to suggest that carbocation 345 (Scheme 4.13) has a greater tendency to undergo Wagner-Meerwein rearrangement to yield 346 than to undergo the competing 3,2-exo-methyl shift to yield 347. Alternatively, it may be that the bromination pathway does initially proceed via 347 to yield enrfo-3,9-dibromo-4-methylcamphor (328), but in the presence of sufficient quantities of bromine, 328 readily undergoes further bromination to yield the observed major product, ertdo-3,9-dibromo-4-(bromomethyl)camphor (332). By contrast, it is interesting to note that enrfo-3-bromocamphor (ent-20) undergoes bromination under similar conditions [Br2 (1.5 eq), CISO3H] to yield enrfo-3,9-dibromocamphor {ent-22) as the major (-70-80%) product {cf. Scheme 4.14)3137,45 Addition of further amounts of bromine and chlorosulfonic acid to the reaction mixture and prolonging the reaction time does not result in significant production of a tribrominated compound analogous to endo-3,9-dibromo-4-(bromomethyl)camphor (332).63 Instead, there is a small increase in the amount of 9 , C H B r 2 Br 2 (2-5 eq.), C I S O 3 H X X X X Br 2 (1 .5eq) ,ClS0 3 H B r 5h eiKfo-3-bromocamphor (ent-20) Q Br 2 (1.5eq),ClS0 3 H 5-8 d enrfo-3,9-dibroniocamphor (ent-22) *%5' Br e#u/0-3,9,lO-tribromo-camphor (ent-32) Q Br 2 (2.2 eq), C1S0 3 H 15h Br 9 f3 Br e«4o-3-bromo-4-methylcamphor (327) B r - 4 ' Br e/tt/0-3,9-dibromo-4-(bromomethyl)camphor (332) Scheme 4.14. Comparison of the Bromination of endo-3-Bromocamphor (ent-20) and endo-3-Bromo-4-methylcamphor (327) under Br 2/C1S0 3H Conditions. 106 ^«rfo-3,9,9-tribromocamphor (350)46d that is formed when excess bromine is present in the reaction mixture. Curiously however, only after the 3,9-dibromocamphor (ent-22) has been isolated and purified by recrystallization, can bromination (Br2, CISO3H) take place to yield evjdo-3,9,10-tribromocamphor (ent-32). A convincing explanation for this unusual, but reproducible observation cannot be readily formulated. Suffice it to say that the factors governing the particular rearrangement pathways undergone by the carbocationic intermediates (e.g. Scheme 4.13) are presently not well understood. iii. Evaluation of the Proposed Bromination Pathway Using endo-3-Bromo-9-deuterio-4-(deuteriomethyl)camphor (351) as a Labelled Substrate. W M = Wagner-Meerwein rearrangement 3,2-exo-Me = 3,2-cxo-methyl shift Scheme 4.15. Reaction Pathway for the Bromination of e«rfo-3-Bromo-9-deuterio-4-(deuterio-methyl)camphor (351). [N.B. In the transformations 354 - » 355 and 357 -4 358, alternative loss of D + can occur in place of H + as indicated in this scheme (see text and Scheme 4.17).] 107 If the sequence of reactions formulated in Scheme 4.13 does in fact represent the pathway taken during the bromination reaction, then two predictions can be made. First, it is predicted that none of the carbon atoms in the starting e/2d0-3-bromo-4-methylcamphor (327) should change their relative positions during the course of the multiple rearrangement-bromination sequence. In other words, if a label such as deuterium or 1 3 C were to be incorporated into the starting material 327, then it should remain on the same carbon in the product 332. To test this hypothesis, it was proposed to study the bromination of the doubly labelled, endo-3-bromo-9-deuterio-4-(deuteriomethyl)camphor (351). According to the proposed reaction pathway it was predicted that the two deuterium labels of 351 should remain on C(9) and C(4') in the final product, endo-3,9-dibromo-9-deuterio-4-(bromodeuteriomethyl)camphor (352). Secondly, the reaction pathway postulated above (Scheme 4.13) for the bromination of endo-3-bromo-4-methylcamphor (327) proposes also the existence of two exocyclic alkene intermediates 344 and 348, which are derived from loss of a proton from the corresponding methyl groups in structures 343 and 346, respectively. However, if ertd<9-3-bromo-9-deuterio-4-(deuteriomethyl)camphor (351) were used as a substrate in the same bromination reaction (cf. Scheme 4.15), the corresponding mechanistic intermediates 354 and 357 can undergo not only similar proton loss, but deuteron loss as well. Whereas the loss of a proton would lead to 343 344 346 348 108 the formation of a -CHDBr group after bromination, loss of a deuteron would yield a -CH2Br group. From previous experiments,463'72 it has been observed that -CH2X and corresponding - C H D X protons (X = H or Br) have slightly different *H NMR chemical shifts. One could therefore use lH NMR spectroscopy as a means for detecting the presence of the two -CHDBr-containing diastereomers and the -CFf2Br-containing by-products. If the -CH.2Br-containing by-products are detected, indirect support for the existence of exocyclic methylene intermediates such as 355 and 358 in the proposed bromination mechanism would thus be gained. At this juncture, we needed to prepare e«<io-3-bromo-9-deuterio-4-(deuteriomethyl)camphor (351), which we wished to use as a probe to study the multiple rearrangement-bromination mechanism outlined in Schemes 4.13 and 4.15. Thus, chemoselective debromination of the 3-bromo substituent in erafo-3,9-bromo-4-(bromomethyl)camphor (332) using zinc powder in 1:1 HOAc-diethyl ether yielded 9-bromo-4-(bromomethyl)camphor (362).72 Reaction of 9-bromo-4-(bromomethyl)camphor (362) with tributyltin deuteride and a catalytic amount of azobis(isobutyronitrile) in refluxing benzene yielded 9-deuterio-4-(deuteriomethyl)camphor (363).72 9 9 9 332 362 363 351 364 (i) Zn, H O A c - E t 2 0 , 0 °C (ii) Bu 3 SnD, AIBN, C ^ , reflux (iii) Br 2 , HOAc, 80 °C (iv) Br 2 , C I S O 3 H , 15 h (v) Bu 3 SnH, AIBN, QsHg, reflux. Scheme 4.16. Conversion of e«rfo-3,9-Dibromo-4-(bromomethyl)camphor (332) to 9-deuterio-4-(deuterio)camphor (363). Conversion of 9-deuterio-4-(deuterio)camphor (363) to Derivatives for Use in Investigating the Mechanism of the Bromination of endo-3-Bromo-4-methylcamphor (327). 109 110 The 400 M H z * H NMR spectrum (Figure 4.2, p. 109) of 9-deuterio-4-(deuteriomethyl)camphor (363) exhibits, most characteristically, four signals between 0.69-1.02 ppm. The two apparent triplets at 1.00 and 0.80 ppm can be assigned to the C(9) or C(4') protons on the basis of the observed multiplicities. Furthermore, the triplet signal at 0.80 showed a correlation with the singlet at 0.69 ppm in the 400 MHz COSY spectrum (cf. Table 5.23, p. 202). This correlation could arise as a result of long-range (47 or W-) coupling between the C(9) and C(8) protons. By elimination, the triplet at 1.00 ppm and the singlet at 0.90 ppm are assigned to the C(4') and C(10) protons, respectively. The chemical shifts of the C(4') and C(9) protons of 363 (1.00 and 0.80 ppm) are shifted upfield relative to the chemical shifts of the corresponding protons of 4-methylcamphor (87) at 1.02 and 0.81 ppm, respectively. In addition, two weak singlets do appear at the latter chemical shifts in the NMR spectrum of 9-deuterio-4-(deuteriomethyl)camphor (363); their significance will be discussed shortly. The signals at 2.08 and 2.03 ppm correspond to the C(3) exo and endo protons, respectively, while the multiplets between 1.30-1.75 ppm can be assigned to the four protons bonded to C(5) and C(6). Noteworthy in the 75 MHz 1 3 C NMR spectrum of 363 is the presence of two triplets at 15.5 and 15.1 ppm which represent, collectively, the C(9) and C(4') carbons. The observed coupling constants for both signals are 19 Hz, and correspond to the one-bond Of) coupling of a 1 3 C (spin y2) nucleus with a deuterium (spin 1) nucleus. Finally, mass spectral data confirm that two deuterium atoms have indeed been incorporated into the product, and that the identity of the product is 9-deuterio-4-(deuteriomethyl)camphor (363). Subsequent treatment of 9-deuterio-4-(deuteriomethyl)camphor (363) with bromine in acetic acid at 80°C yielded enrf«?-3-bromo-9-deuterio-4-(deuteriomethyl)camphor (351), whose structure was confirmed by *H and 1 3 C NMR spectroscopy and mass spectrometry. With the dideuterated bromocamphor derivative 351 in hand, we were now ready to submit 351 to the conditions of the bromination reaction of interest (cf. Scheme 4.16, step (iv)), identify the products that would be formed in the reaction, and study the fate of the deuterium labels in 351 I l l after the reaction. Thus, treatment of e«rfo-3-bromo-9-deuterio-4-(deuteriomethyl)camphor (351) with bromine (2.2 eq) in chlorosulfonic acid yielded a product mixture in which the major product (-90-95%) was purified by chromatography and tentatively identified as endo-3,9-dibromo-9-deuterio-4-(bromodeuteriomethyl)camphor (352) by analogy to the corresponding reaction involving the unlabelled compound 332. The 400 MHz J H NMR spectrum of endo-3,9-dibromo-9-deuterio-4-(bromodeuterio-methyl)camphor (352; cf. Figure 4.3, p. 112) was recorded and assigned by comparison with that for the corresponding unlabelled compound, ertrfo-3,9-dibromo-4-(bromomethyl)camphor (332; cf. Figure 4.1, p. 102). The spectra for 352 and 332 are similar. Both spectra show signals at 1.24 and 1.04 ppm that can be assigned to the C(8) and C(10) protons of 352 and 332. Not unreasonably, the signals for the H(3 e m), H(5ex0), H(5 e „^ 0 ) , H(6 e m ) , and H(6 e „^ 0 ) protons are also at the same chemical shifts in both spectra. The most pronounced difference between the two spectra, however, occurs in the region in which the C(9) and C(4') protons resonate, that is, between 3.4—4.1 ppm. To explain that there are four signals associated with the C(9) and C(4') protons in 352 one must be mindful that each of C(9) and C(4') in enc?o-3,9-dibromo-9-deuterio-4-(bromodeuteriomethyl)camphor (352) are stereocenters originating from the loss of either diastereotopic C(9) or C(4') proton from the intermediate carbocations 354 or 357, respectively (see Schemes 4.15 and 4.17). Consequently, depending on the configurations of C(9) and C(4') in 352, there could arise four different signals for the two C(9) and C(4') protons in 352, as is observed. 112 113 Whereas in the spectrum of ertdo-3,9-ctibromo-4-(bromomethyl)carnphor (332) the four signals between 3.4^4.1 ppm representing the diastereotopic protons of C(9) and C(4') are doublets, labelled A through D in Fig. 4.1 (p. 102), one notices that in the spectrum of the deuterated analogue 352, the same four signals are now apparent singlets, labelled A' through D' in Figure 4.3 (p. 112). The change in multiplicity in these four particular signals, which were previously assigned to H(9) and H(4') in 332, suggests that the deuterium labels reside on C(9) and C(4) of 352 and thus provides support for our prediction (p. 107) that the carbon atoms of 351 (or 327) do not change their relative positions over the course of the bromination. In addition, we proposed that not only can either proton from the original C(9) and C(4') be lost from each of intermediates 354 and 357 (Scheme 4.17), the deuterium labels can be lost Scheme 4.17. Possible Fates of Carbocation 354 During the Bromination of endo-3-Bromo-9-deuterio-4-(deuteriomethyl)camphor (351). [N.B. Carbocation 357 (Scheme 4.15) behaves similarly to provide analogous carbocations 358a,b,c and 359a,b,c] as well. If the deuterium labels are indeed lost, the resulting brominated intermediates 356c and 359c (Scheme 4.17) would have -CH2Br groups at one or both of C(9) or C(4'). As in the lE 114 NMR spectrum of endo-3,9-dibromo-4-(bromomethyl)camphor (332; cf. Figure 4.1, p. 102), each diastereotopic proton of the -CFf2Br groups would appear as a doublet at a chemical shift that is distinct from that of the corresponding signal of the compound bearing a -CHDBr group. Indeed, the 400 MHz lH NMR spectrum provides evidence that compounds containing -CH2Br groups are present. The four small signals in the spectrum (Figure 4.3, p. 112), marked A " through D" and assigned to the -CH2Br protons, can be interpreted as being parts of doublets [cf. Figure 4.1, p. 102] in which the right half of each doublet has been obscured by the adjacent singlet (A' through D') arising from the corresponding proton in the deuterated compound 352. In fact, the chemical shifts of the four weak signals (A" through D") in the spectrum of the product mixture correspond to those of signals A through D in the spectrum of authentic endo-3,9-dibromo-4-(bromomethyl)camphor (332) [cf. Figure 4.1, p. 102]. The purity of the starting material, 9-deuterio-(4-deuteriomethyl)camphor (363) must also be taken into account when assessing the significance of the appearance of -CH2Br-containing compounds. 9-Deuterio-4-(deuteriomethyl)camphor (363) was prepared via the reaction of 9-bromo-4-(bromomethyl)camphor (362) with commercially available tributyltin deuteride,149 whose deuterium isotopic purity was claimed by the suppliers (Fluka) to be >97%. The small amount (<3%) of tributyltin hydride present in the reagent resulted in the substitution of one or both of the bromo groups in 362 with a hydrogen rather than a deuterium atom. In practice, the resulting minor by-products could not be separated from the desired 9-deuterio-4-(deuteriomethyl)camphor (363), and consequently had to be carried through the subsequent series of reactions. At this point, we wished to determine the fraction of non-deuterated by-products present in our sample of 9-deuterio-4-(deuteriomethyl)camphor (363). Closer examination of the *H NMR spectrum of 9-deuterio-4-(deuteriomethyl)camphor (363), assigned previously (p. 110), reveals that it differs from the spectrum of 4-methylcamphor (87) in that the resonances for the C(9) and C(4') deuteriomethyl groups at 0.80 and 1.00 ppm are broad triplets due to coupling of the C(9) and C(4') protons with the respective geminal deuterium atoms. It is assumed that the 115 chemical shifts of each pair of diastereotopic protons on C(9) and C(4') are coincident. Slightly downfield of each of these triplets are two small singlets, at 0.81 and 1.02 ppm. It is noteworthy that the chemical shifts of these two singlets are coincident with those for the C(9) and C(4') methyl groups in 4-methylcamphor (87). It is believed that the two residual signals arise from the by-products formed as a result of the reaction of 9-bromo-4-(bromomethyl)camphor (362) with the tributyltin hydride impurity in the tributyltin deuteride reagent. For the sake of convenience in the subsequent discussion, these two signals will henceforth be termed the 'protio signals', arising from the 'protio impurity.' Likewise, the adjacent triplets will be termed the 'deuterio signal.' It was determined through comparison of the normalized integrals of the protio and deuterio signals that the protio impurities accounted for (4+2)% of the total product mixture. The uncertainty in the figure arises mainly from the uncertainties associated with measuring the integrals on the spectra. Thus, in consideration of the protio impurity already present in the starting 9-deuterio-4-(deuteriomethyl)camphor (363), we could not immediately claim that the presence of de-deuterated by-products in the e/irfo-3,9-dibromo-9-deuterio-4-(bromodeuteriomethyl)camphor (352) product mixture provided support for the proposal that deuterium loss can occur during the bromination process; the de-deuterated by-products could, after all, just have been derived from the protio impurity in the original 9-deuterio-4-(deuteriomethyl)camphor (363) sample. However, we realized that the same amount of protio impurity present in the original 9-deuterio-4-(deuteriomethyl)camphor (363) sample must be carried through the synthetic sequence to endo-3,9-dibromo-9-deuterio-4-(bromodeuteriomethyl)camphor (352) because no loss of deuterium was expected in the intermediate conversion of 363 to ertdo-3-bromo-9-deuterio-4-(deuteriomethyl)camphor (351). Thus, if a significant increase in the amount of protio impurity in the e/i£/o-3,9-dibromo-9-deuterio-4-(bromodeuteriomethyl)camphor (352) product mixture was noted, we could then attribute the increase to have originated from the bromination reaction (351 -> 352). 1 Having already estimated the amount of protio impurity in the original 9-deuterio-4-(deuteriomethyl)camphor (363) sample, we now sought to determine the relative amount of protio impurity present in the endo-3,9-dibromo-9-deuterio-4-(bromodeuteriomethyl)camphor (352) mixture. For this purpose, the apparent singlet (B") at 3.73 ppm [H(9) signal; cf. Figure 4.3] is assumed to represent the left-hand branch of a doublet that would normally be present in a spectrum of authentic e«do-3,9-bromo-4-(bromomethyl)camphor (332; cf. Figure 4.1); the missing right-hand branch of the doublet is obscured, presumably, by the adjacent, more intense deuterio signal (B'). For simplicity, it is also assumed that the integrations of both branches of the doublet are equal. The fraction of protio impurity in the total sample of 352, which comprises both the protio and deuterio compounds, can be estimated by dividing twice the integral of B" by the sum of the integrals of B' and B". It was thus determined that the amount of protio by-products present in the product mixture is approximately (25±8)%. The error in this value takes into account the uncertainty in measurement of the integrals on the spectrum and also the assumption that the integration of the obscured right-hand branch of the doublet is the same as that of the observed left-hand branch (B"). At this point, we decided to convert ertdo-3,9-bromo-9-deuterio-4-(bromodeuterio-methyl)camphor (352) into 9-bromo-9-deuterio-4-(bromodeuteriomethyl)-camphor (364) (Zn, HOAc-Et20) and thence back to 9-deuterio-4-(deuteriomethyl)camphor (363) (Bu3SnH, AIBN, C6H6, reflux). Over the course of these two subsequent transformations the protio content determined above for the sample of endo-3,9-bromo-9-deuterio-4-(bromodeuteriornethyl)-camphor (352) was not expected to change. Thus, it was expected that similar comparisons of the integrals of appropriate signals in the *H NMR spectra of 363 and 364 could serve as a means for verifying the above determination of the protio content in 352. Examination of the *H spectrum for 9-bromo-9-deuterio-4-(bromodeuteriomethyl)-camphor (364) provided further estimates for the protio content in the sample. From the H(4') 1 17 i I i . . . . i . . . . i r 2.00 1.50 .1.00 0.50 0 8 (ppm) i I i • • . — 2.00 1.50 1.00 0.50 0 S (ppm) Figure 4.4: 400 MHz lH NMR Spectra of 9-Deuterio-4-(deuteriomemyl)carnphor (363) recorded before (top) and after (bottom) the bromination cycle (cf. Scheme 4.16). 118 signals at 3.95 (protio) and 3.90 ppm (deuterio), the protio content was estimated to be (27±7)% while the H(9) signals at 3.30 (protio) and 3.26 (deuterio) ppm provided an estimate of (29±7)%. Similarly, in the spectrum of 9-deuterio-4-(deuteriomethyl)camphor (363), prepared from 9-bromo-9-deuterio-4-(bromodeuteriomethyl)camphor (364), the protio content was found to be (25±7)%, which is consistent with the values obtained above from the spectra of endo-3,9-bromo-9-deuterio-4-(bromodeuteriomethyl)camphor (352) and 9-bromo-9-deuterio-4-(bromo-deuteriomethyl)camphor (364). Moreover, the increase in protio content in 363 [(25±7)% from (4±2)%; cf. p. 115] before and after the bromination cycle 363 -> 351 -> 352 -» 364 -» 363 (Scheme 4.16) is evident when the *H NMR spectra (Figure 4.4, p. 117) of the two samples of 9-deuterio-4-(deuteriomethyl)camphor (363) are compared. In summary, after the bromination of e/id<>3-bromo-9-deuterio-4-(deuteriomethyl)-camphor (351) it was found that the content of the protio impurity in the product (352) is roughly (25+7)%, which is significantly more than the amount of protio impurity (4±2)% present in the original 9-deuterio-4-(deuteriomethyl)camphor (363) sample. The marked increase in protio impurity after the bromination reaction can be attributed to the loss of a deuteron from intermediates 354 and 357 (Scheme 4.15) in the proposed mechanism, and thus provides indirect support for our proposal that incorporation of bromine into end0-3-bromo-4-methylcamphor (327) involves exocyclic methylene intermediates such as 344 and 348 (Scheme 4.13). Moreover, as described earlier (pp. 111-113), that the product arising from the bromination of ertrfo-3-bromo-9-deuterio-4-(deuteriomethyl)camphor (351) was shown to be endo-3,9-dibvomo-9-deuterio-4-(bromodeuteriomethyl)camphor (352) suggests that the deuterium atoms that were present in the starting e/irfo-3-bromo-9-deuterio-4-(deuteriomethyl)camphor (351) have not changed their relative positions in the product (352). These two results are consistent with, and therefore support the proposed mechanism for the bromination of cndo-3-bromo-9-deuterio-4-(deuteriomethyl)camphor (351) and eAzdo-3-bromo-4-methylcamphor (327) outlined in Scheme 4.15 and 4.13, respectively. As an extension to this work, similar tracer studies using other 119 deuterium-labelled 4-methylcamphor derivatives could be used to obtain further evidence to support the validity of the proposed bromination mechanism. iv. Future Directions Current efforts in our laboratory151 are directed towards the development of a synthetic route from 9-bromo-4-(bromomethyl)camphor (362) to the bicyclic enone ent-328. Oxidation of 9-bromo-4-(bromomethyl)camphor (362) with selenium dioxide in refluxing acetic anhydride66 yielded 9-bromo-4-(bromomethyl)camphorquinone (365), which also can be regarded in an alternative representation, after renumbering, as 9,10-dibromo-4-methylcamphorquinone (366). Like 9,10-dibromocamphor (33, Scheme 1.9, p. 13), 9,10-dibromo-4-methylcamphorquinone (366) also possesses an «,a-disubstituted-j3-bromoketone sub-unit that makes possible the iv ent-32% Scheme 4.18. Proposed Use of 4-Methylcamphor and Derivatives as Intermediates in Triterpenoid and Steroid Synthesis. application of a Grob fragmentation reaction (NaOMe, MeOH; or K O H , MeOH; K 2 C O 3 , DMF, then C H 3 I ) 3 9 to yield bromo-keto-ester (368). It is anticipated that bromo-keto-ester 368 can be transformed into bicyclic enone ewf-328, a valuable intermediate in our projected synthetic route to the euphane and tirucallane triterpenoids. Furthermore, by starting with the enantiomeric 4-methylcamphor (ent-87), it would be possible to obtain bicyclic enone 328 which could also be used to gain access to the lanostane triterpenoids and 14a-methyl steroids. Chapter 5 Experimental Section 121 5. Experimental Section (a) General Experimental All reactions involving air- or moisture-sensitive reagents were conducted under argon atmosphere. Where no reaction temperature has been noted in a particular experimental procedure, that reaction was carried out at room temperature [(22 ± 2) °C]. Unless specified otherwise, T H F and diethyl ether were distilled 1 5 2 over sodium/benzophenone while dichloromethane, benzene, toluene, acetonitrile, triethylamine, diisopropylamine, piperidine and dimethyl sulfoxide were distilled over calcium hydride. Methanol was distilled from magnesium turnings in the presence of several crystals of iodine. Methanesulfonyl chloride was distilled over phosphorus pentoxide. Ethylene glycol was distilled over calcium oxide and stored over 4 A molecular sieves. Methyl iodide, allyl bromide, 2-methyl-l,3-dithiane, and D B U were passed through a short (~5 x 0.5 cm) column of oven-dried (160 °C) basic alumina (Brockmann Activity I) immediately prior to use. CDCI3 was stored over anhydrous potassium carbonate. PPTS was prepared and purified according to the method outlined by Grieco and co-workers.92b L D A was prepared in situ according to the method described by White and Heathcock.1 5 3 For ozonolysis reactions, ozone was generated (-4% O3 in O2) using a Welsbach Model T-23 laboratory ozonator. Extraction solvents and all other reagents were used as received. The concentrations of commercially obtained butyllithium solutions were determined periodically by the method of Kofron and B a c l a w s k i . 1 5 4 a Solutions of lithium triethylborohydride were used as received. If desired, however, concentrations of organoboron reagents can be determined by the method outlined by Brown. 1 5 4 b Gas-liquid chromatography (GLC) was performed on a Hewlett-Packard HP-5830A gas chromatograph employing an HP-1 (0.2 mm x 12 m x 0.33 /im) capillary column. Thin-layer chromatography (TLC) was performed on commercially available aluminum or plastic sheets pre-coated with silica gel 60 F254 (Merck 5554, 0.2 mm thickness). Visualization of thin-layer chromatograms was accomplished with ultraviolet light (254 nm), 2% phosphomolybdic acid 122 spray, or 1% p-anisaldehyde spray. Radial chromatography was performed on a Harrison Research Chromatotron®, Model 7924T, using circular glass plates (1 mm or 2 mm thickness x 11.25 cm radius) coated with Merck Silica Gel 60 F254 containing gypsum. Flash column chromatography was performed according to the method reported by Still and co-workers.155 The evaporation of solvents under reduced pressure (~20-30 Torr) was accomplished using a Biichi rotary evaporator. All 400 MHz lH and 100 MHz 1 3 C NMR spectra were recorded on a Bruker WH-400 spectrometer while 75 MHz 1 3 C NMR spectra were recorded on a Varian XL-300 spectrometer, and 200 MHz ! H and 50 MHz 1 3 C NMR spectra on an Bruker AC-200 spectrometer. COSY and difference NOE experiments were performed on the Bruker WH-400 instrument while HETCOR experiments were performed on the Varian XL-300 instrument. NMR signal positions (S) are reported in parts per million and are referenced to the residual proton signal of C H C I 3 (7.24 ppm) or the carbon signal of 1 3 £DCl3 (77.0 ppm), as appropriate. Throughout this chapter, the abbreviations used to denote NMR signal multiplicities are as follows: s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), br (broad), dd (doublet of doublets), dt (doublet of triplets), ddd (doublet of doublet of doublets), etc. In referring to lH NMR signals for diastereotopic protons, the notations H ( X A ) and H(XB) have been used to denote signals resonating at higher and lower field, respectively. Infrared spectra were recorded on a Perkin-Elmer Model 1710 Fourier transform spectrophotometer. Abbreviations that have been used in the experimental section to describe IR signals are: br (broad), v (stretching vibration), sym (symmetric vibration), and asym (asymmetric vibration). Low and high resolution electron impact mass spectra were acquired on a Kratos MS-50 mass spectrometer while desorption chemical ionization mass spectra were recorded on a Delsi Nermag R-10-10C instrument. Melting points were measured on a Reichert hot stage and are uncorrected. Specific rotations were recorded on a Jasco J-710 or Perkin-Elmer 141 spectropolarimeter in a 0.1 or 1.0 dm cell, respectively. Microanalyses were 1 2 3 performed by Mr. P. Borda of the UBC Microanalytical Laboratory on a Carlo-Erba C H N elemental analyzer, model 1106 or Fisons CHN-0 elemental analyzer, model 1108. (b) Safety Considerations All chemical manipulations described in this chapter were conducted in a well-ventilated fumehood in accordance with guidelines outlined in Material Safety Data Sheets (MSDSs) for individual reagents. Appropriate personal protective equipment was worn at all times. The toxicity and hazards of all newly synthesized compounds are unknown, and it is therefore advisable that such compounds be handled with caution. The disposal of chemicals was carried out in accordance with guidelines prescribed by the University of British Columbia Department of Health, Safety & Environment (formerly Occupational Health & Safety) and by accepted literature methods.156 (c) Experimental Procedures The experimental procedures in the following section are arranged in order of occurrence in appropriate synthetic plans. Selected unsuccessful procedures and procedures for compounds that are not part of a finalized synthetic plan have been relegated to the Appendix. The Index of Experimental Procedures (p. xi) may be used to assist in locating specific procedures. (-)-Camphor (ent-9) To a solution of (-)-borneol (159; 171.3 g, 1.110 mol) in acetone (400 mL) at 0 °C was added, dropwise over 1 h, Jones reagent [prepared from chromium(VI) oxide (104.0 g, 1.040 mol), water (350 mL), and concentrated sulfuric acid (100 mL) [CAUTION: The addition of concentrated sulfuric acid to the solution of chromium(VI) oxide in water is exothermic. 159 ent-9 124 The use of an external ice-water cooling bath is strongly advised during the preparation of the Jones reagent]. The dark orange-green reaction mixture was stirred at 0 °C for 2 h after which saturated aq. NaHS03 (-200 mL) was added. The reaction mixture was poured into water (-500 mL). The organic phase was withdrawn while the aqueous phase was extracted with Et20 (3 x 500 mL). The organic extracts were washed with water (4 x 500 mL), neutralized with saturated aq. NaHCC>3 (2 x 500 mL), washed with brine (3 x 500 mL), dried over anhydrous MgS04, and concentrated under reduced pressure to yield (-)-camphor (ent-9) as a volatile, white solid (165.1 g, 97%) that could be used directly in the next reaction without further purification; mp 177-179 °C (lit. 178-180 ° C ; 1 5 6 ) ; [a]25 -43.7 (c 1.02, EtOH) (lit157'. [a]2£ -43 (c 10, EtOH)). ! H N M R (CDCI3, 400 MHz): 8 2.32 (ddd, J = 17.0, 5.0, 2.5 Hz, 1H; H(3exo)), 2.10 (dd, / = 5.0, 5.0 Hz, 1H; H(4)), 1.92-2.01 (m, 1H; C(5exo)), 1.86 (d, J = 17.0, 5.0 Hz, 1H; HOendo), 1-69 (ddd, J = 14.0, 14.0, 4.5 Hz, 1H; H(6eXo)), 1.29-1.45 (m, 2H), 0.96 (s, 3H; H(9)), 0.92 (s, 3H; H(10)), 0.84 (s, 3H; H(8)). IR (neat film): 2970, 2915, 2890,1735 (v C =o) cm"1. EIMS m/z (rel intensity): 152 ( M + ; 26.7), 110 (13.0), 109 (28.9), 108 (52.8), 95 (100). Exact mass calcd for C10H16O 152.1201 , found 152.1204. Anal. Calcd for C i 0 H i 6 O : C, 78.90; H, 10.59. Found: C, 78.75; H, 10.56. (-)-cndo-3-Bromocamphor (ent-20) Br ent-9 ent-20 To a solution of (-)-camphor (ent-9; 143.0 g, 0.939 mol) in glacial acetic acid (500 mL) at 80 °C was added, dropwise over 40 min, a solution of bromine (58 mL, 180 g, 1.1 mol) in 125 glacial acetic acid (60 mL). The red-orange solution was stirred at 80 °C for 18 h, allowed to cool to room temperature, and poured cautiously into a saturated aq. NaHS03 solution (-250 mL). The aqueous solution was decanted and extracted with Et20 (3 x 500 mL) while the precipitated crude product was dissolved in Et20 (250 mL). The combined organic solutions were washed with water (2x1 L), neutralized with saturated aq. NaHOC»3 (3 x 500 mL), washed with brine (3 x 500 mL), dried over anhydrous MgSC»4, and concentrated under reduced pressure to a light orange-brown solid. Recrystallization of the orange-brown solid from 95% ethanol yielded endo-3-bromocamphor (ent-20) as white crystals (154.1 g, 71%). Spectroscopic data obtained for ent-20 were in agreement with those reported in the literature.30'65 (-)-enrfo-3,9-Dibromocamphor (ent-22)45 (-)-enrfo-3,9,10-Tribromocamphor (ent-32)45 (-)-9,10-Dibromocamphor (ent-33)45 (+)-Hydroxy-acid (e«*-37) 3 9 ent-20 ent-2245 ent-3245 ent-3345 1. K O H , D M S O - H 2 0 (9:1), 90 °C 2. 6 N H C 1 H ent-31 ,39,45 The title compounds ent-22, ent-32, ent-33, and ent-31 were prepared according to literature methods.3 9'4 5 All spectroscopic data were in agreement with those reported in the literature.37-45 126 (+)-Hydroxy-ester (160)45 H C 0 2 H K 2 C ° 3 . D M F ; C H 3 I ent-31 Hydroxy-ester 160 3 9 ' 4 5 was prepared according to a method reported earlier by our research group 4 5 Purification of hydroxy-ester 160 was accomplished via flash column chromatography (5% EtOAc-CH2Cl2). Spectroscopic data obtained for 160 were in agreement with those reported in the literature.45 MJutyldiphenylsilyloxy-ester (162b) To a solution of hydroxy-ester (160)39*45 (6.4421 g, 32.49 mmol) and imidazole (11.06 g, 162.4 mmol) in spectro grade DMF (40 mL) was added r-butyldiphenylsilyl chloride (9.9 mL, 11 g, 39 mmol). 9 3 The reaction mixture was stirred at room temperature for 5 h after which it was partitioned between water (200 mL) and Et20 (100 mL). The aqueous phase was extracted further with Et20 (2 x 50 mL). The combined extracts were then washed with water (50 mL) and brine (3 x 50 mL), dried over anhydrous MgSC»4, and concentrated under reduced pressure to a colorless oil. Further purification by flash column chromatography (5% EtOAc-pet. ether) yielded pure silyloxy-ester (162b) as a colorless oil (13.4679 g, 95%). 1H N M R (CDCI3, 400 MHz): 8 7.65-7.72 (m, 4 H ; - Q H 5 ) , 7.35-7.45 (m, 6H;-CgHs), 4.89 (bs, 1H; = C H A H B ) , 4.72 (bs, 1H; = C H A H B ) , 3.68 (s, 3 H ; - C O ? M e \ 3.49 (d, J = 10.0 127 Hz, 1H; H(6)A), 3.44 (d, J = 10.0 Hz, 1H; H(6)B), 2.61 (dd, / = 15.0, 4.0 Hz, 1H; H(10)A), 2.49-2.59 (m, 1H; H(l)); 2.23-2.44 (m, 2H; H(3)A, H(3)B), 2.12 (dd, / = 15.0, 10.0 Hz, 1H; H(10)B), 1.85-1.94 (m, 1H; H(2)A), 1.24-1.37 (m, 1H; H(2)B), 1.06 (s, 9H; BuO, 0.92 (s, 3H; C(5)-CH3). 13C N M R (CDC1 3 , 75 MHz): 8 174.0 (C=0), 157.9 (C(4)=CH2); 135.7, 133.5, 129.5, and 127.6 (aromatic carbons); 105.5 (C(4)), 70.8 (C(6)), 51.4 (-OCH3), 48.6, 42.2 (C(l)), 35.9, 32.2, 29.2, 26.8 (C(CH3)3), 19.7 ( £ ( C H 3 ) 3 ) , 19.3 (C(5)-CH3). IR (neat film): 3071 (v = C- H (aromatic)), 3060 (v = C- H (aromatic)), 2956,2894, 2858, 1741 (vC=o), 1650 (v c =c), 1590, 1472, 1429, 1194 (vc_o) cnr*. EIMS m/z (rel intensity): 436 (0.1; M + ) , 405 (1.7; (M - OMe) +), 379 (87.3; (M -f-Bu) +), 347 (9.1), 318 (2.5), 213 (100). Exact mass calcd for C3iH4205Si 436.2434 , found 436.2428. Anal. Calcd for C 2 7 H 3 6 0 3 S i : C, 74.27; H, 8.31. Found: C, 74.31; H, 8.27. Keto-ester (163b) A stream of ozonized oxygen (-4% 0 3 in O2) was bubbled into a solution of silyloxy-ester (162b) (12.4231 g, 28.45 mmol) in 1:1 CH 2 Cl2-MeOH (200 mL) at -78 °C until a faint blue color persisted (~1 h). Excess ozone was purged with oxygen gas (-10 min). Dimethyl sulfide (20 mL) was added and the reaction mixture was allowed to warm to room temperature over 12 h. The solution was concentrated to a clear, pale yellow oil that was then purified by flash column chromatography (20% Et20-pet. ether) to yield pure keto-ester (163b) as a viscous, clear, colorless oil (11.4776 g, 92%) 162b 163b 128 1H N M R (CDCI3, 400 MHz): 8 7.61-7.67 (m, 4H; -QH5), 7.33-7.44 (m, 6H; -C6H5), 3.78 (d, J = 9.2 Hz, 1H; H(6A)), 3.68 (s, 3H; -OCH3), 3.32 (d, J = 9.2 Hz; H(6B)), 3.02-3.12 (m, 1H; H(10A)), 2.34-2.48 (m, 2H; H(10B), H(3A)), 2.12-2.30 (m, 3H; H(l), H(2A), H(3B)), 1.44-1.58 (m, 1H; H(2B)), 0.99 (s, 9H; Buf), 0.71 (s, 3H; C(5)-CH3). 13C N M R (CDCI3, 50 MHz): 8 217.5 (C=0), 172.3 (C0 2Me), 135.7, 132.3, 129.7, 127.7, 66.2 (C(6)), 53.0, 51.6, 38.2, 37.2, 35.0, 26.8 (-C(CH 3 ) 3 ) , 25.4, 19.2, 13.8 (C(5)-CH3). IR (neat film): 3073, 3050, 2948,2858,1741 (vc=o), 1467,1428,1101 (vc_o) cm-l. EIMS mlz (rel intensity): 407 (0.7; (M - OMe) +), 381 (25; (M - f-Bu)+), 349 (2.1), 321 (1.8), 307 (4.5), 105 (100). Exact mass calcd for C22H25C>4Si (M - r-Bu)+ 381.1522, found 381.1523. Anal. Calcd for C26H3404Si: C, 71.19; H, 7.81. Found: C, 70.99; H, 7.91. Table 5.1. Spectral Data from COSY Spectrum of Keto-ester 163b. 400 MHz J H NMR Spectrum Assign- COSY Correlations Assign-Signal Positions [8 (ppm)] ment Signal Positions [8 (ppm)] ment 7.61-7.67 -C6H5 7.33-7.44 -C6H5 7.33-7.44 -C6H5 7.61-7.67 -C6H5 3.78 H(6 A ) 3.32 H ( 6 B ) 3.32 H(6 B ) 3.78 H(6A) 3.02-3.12 H(10A) 2.34-2.48,2.12-2.30 H(10B) H(l) 2.34-2.48 H(10 B ) , H(3A) 3.02-3.12, 2.12-2.30, 1.44-1.58 H(10A) H(2 A ,B) H(3 B ) 2.12-2.30 H(l), H(2 A , 3 B ) 3.02-3.12, 2.34-2.48, 1.44-1.58 H(10A,B) H(3A), H ( 2 B ) 1.44-1.58 H(2 B ) 2.34-2.48,2.12-2.30 H(l , 2A) H(3A .B) 129 Ketal-ester (164b) H H 10 C 0 2 M e (CH 2 OH) 2 ,p -TsOH C6H6, reflux I O 1 L^/ OTBDPS 164b C 0 2 M e O OTBDPS 163n To a solution of keto-ester (163b) (11.3824 g, 25.95 mmol) in dry, distilled benzene (200 mL) was added dry ethylene glycol (29 mL, 32 g, 519.0 mmol) and p-toluenesulfonic acid (0.4936 g, 2.595 mmol). The heterogeneous mixture was stirred vigorously at reflux in a Dean-Stark apparatus for 18 h. The reaction mixture was cooled to room temperature, diluted with Et20 (200 mL) and poured into water (~250 mL). The organic phase was separated while the aqueous phase was extracted once more with Et20 (200 mL). The combined organic solutions were washed with water (250 mL), saturated aq. NaHCC>3 (250 mL), and brine (3 x 250 mL), dried over anhydrous MgSCU, and concentrated to yield a clear, straw yellow oil. Subsequent purification by flash column chromatography (20% EtOAc-pet. ether) yielded pure ketal-enone (164b) as a viscous, clear, colorless syrup (11.4846 g; 92%); [a]2* -17.7 (c 0.793, CHC13). ! H N M R ( C D C I 3 , 4 0 0 MHz): 8 7.67-7.76 (m, 4 H ; -CfiHs), 7.32-7.46 (m, 6 H ; - C 6 H 5 ) , 3.72-3.84 (m, 4 H ; - O C H 2 C H 2 O - ) , 3.60-3.70 (m, 2H; H(6A), H(6B)), 3.62 (s, 3 H ; C C b M e l 2.72 (dd, / = 15, 4 Hz, 1 H ; H ( 1 0 A ) ) , 2.51-2.62 (m, 1 H ; H(l)), 2.17 (dd, / = 15, 11 Hz, 1 H ; H ( 1 0 B ) ) , 1.85-2.01 (m, 1 H ; H(2A)), 1.78-1.84 (m, 1 H ; H(3A)), 1.64-1.67 (m, 1 H ; H(3B)), 1.27-1.40 (m, 1H; H(2B)), 1.06 (s, 9 H ; Buf), 0.97 (s, 3 H ; C(5)-CH 3). 13C N M R ( C D C I 3 , 7 5 MHz): 8 173.6 ( £ 0 2 M e ) , 135.6,133.6,129.5,127.5,118.8 (C(4)), 68.1 (C(6)), 64.6 (ketal - O C H 2 C H 2 0 - ) , 64.2 (ketal - O C H 2 C H 2 O - ) , 51.2 ( - O C H 3 ) , 49.5 (C(5)), 40.0 (C(l)), 36.9 (C(10)), 33.4 (C(3)), 26.9 (-C(CH 3 ) 3 ) , 25.9 (C(2)), 19.3 (-C(CH 3 ) 3 ) , 13.6 (C(5)-CH3). 130 IR (neat film): 3072 ( V = C - H ) . 3055 ( V = C _ H ) , 2949, 2873, 1739 (vc=o). 1589, 1470, 1429, 1152, 1099, 1005 cm-1 EIMS mlz (rel intensity): 451 ((M - OMe) +; 77), 425 ((M - Bu') + ; 98), 395 (8), 381 (55), 349 (9), 321 (12), 307 (11), 271 (6), 243 (17), 213 (100). Exact mass calcd for C 2 4H 2 90 5 Si (M - Bu')+: 425.1784, found 425.1786; Exact mass calcd for C27H 350 4Si (M - OMe) +: 451.2304, found 451.2308; Anal. Calcd for C28H3 8 0 5 Si : C, 69.67; H , 7.93. Found: C, 69.58; H , 7.96. Table 5.2. Spectral Data from COSY Spectrum of Ketal-ester 164b. 400 M H z l H N M R Spectrum Signal Positions [8 (ppm)] Assign-ment COSY Correlations Signal Positions [8 (ppm)] Assign-ment 7.67-7.76 -C6H5 7.32-7.46 -QsHs 7.32-7.46 -C6H5 7.67-7.76 - C 6 H 5 2.72 H(10A) 2.51-2.62, 2.17 H(l), H(10B) 2.51-2.62 H ( l ) 2.72, 2.17 H(10A.B), 2.17 H(10B) 2.72, 2.51-2.62 H(10A), H(l) 1.85-2.01 H(2A) 1.78-1.84, 1.64-1.67, 1.27-1.40 H(3 A ,B), H(2B) 1.78-1.84 H(3A) 1.85-2.01, 1.64-1.67, 1.27-1.40 H(3B), H(2A ,B) 1.64-1.67 H(3B) 1.85-2.01,1.78-1.84, 1.27-1.40 H(3A), H(2A .B) 1.27-1.40 H(2B) 1.85-2.01, 1.78-1.84,1.64-1.67 H(2A) H(3A ,B) 131 Table 5.3. Spectral Data from HETCOR Spectrum of Ketal-ester 164b. 75 MHz 1 3 C NMR Spectrum Signal Positions [SQ (ppm)] Assign-ment HETCOR Correlations Signal Positions [S H (ppm)] Assign-ment 135.6, 133.6, 129.5, 127.5 -C6H5 7.67-7.76, 7.32-7.46 -C6H5 68.1 C(6) 3.60-3.70 H(6A,6B) 64.6 ketal 3.72-3.84 ketal 64.2 ketal 3.72-3.84 ketal 51.2 -CO?Me 3.62 -COoMe 40.0 C(l) 2.51-2.62 H(l) 36.9 C(10) 2.72, 2.17 H(10A) H(10B) 33.4 C(3) 1.78-1.84, 1.64-1.67 H(3A,3B) 26.9 -CMe3 1.06 - C M e i 25.9 C(2) 1.85-2.01, 1.27-1.40 H(2A,2B) 13.6 C(5)-Me 0.97 C(5)-Me Ketal-ester (165): Stereoselective Alkylation of Ketal-ester (164b) with Methyl Iodide ¥ H I C 0 2 M e 1. L D A , T H F , - 7 8 ° C 2. CH3I, - 7 8 ° C —> r.t. 164b OTBDPS C 0 2 M e OTBDPS To an ice-cold solution of diisopropylamine (0.73 mL, 0.53 g, 5.2 mmol) in THF (5 mL) was added n-butyllithium (3.35 mL, 1.6 M in hexane, 5.19 mmol) in one portion. The colorless solution was stirred at 0 °C for 40 min and then cooled to -78 °C. After ~5 min, a solution of ketal-ester (164b) (2.0879 g, 4.326 mmol) in THF (10 mL) was added by cannula. After a further 1.0 h, methyl iodide (0.32 mL, 0.74 g, 5.2 mmol) was added. The reaction mixture was stirred at -78 °C for 2 h and then allowed to warm to room temperature, at which it was stirred for 15 h. Water (20 mL) was added, cautiously at first, and the organic phase was separated. 132 The aqueous phase was extracted with ether (3 x 20 mL). The combined extracts were washed with brine (3 x 50 mL), dried over anhydrous MgSC»4 and concentrated to a pale yellow oil. Subsequent purification by flash column chromatography (10% EtOAc-pet. ether) yielded ketal-ester (165) as a clear, colorless oil (2.0409 g, 95%). 1H N M R (CDC1 3, 400 MHz): 8 7.65-7.70 (m, 4H; -C&5), 7.33-7.44 (m, 6H; -C(Ms\ 3.79-3.90 (m, 4H; - O C H 2 C H 2 0 - ) , 3.68 (d, J = 8 Hz, 1H; H(6A)), 3.36 (d, J = 8 Hz, 1H; H(6B)), 3.27 (s, 3H; -COoMcX 2.47 (dq, J = 9.5, 6.9 Hz, 1H; H(10)), 2.28-2.38 (m, 1H; H(l)), 1.71-1.85 (m, 3H; H(3A), H(3b), H(2 a)), 1.28-1.35 (m, 1H; H(2B)), 1.08 (d, J = 6.9 Hz, 3H; C(10)-CH3), 1.04 (s, 9H; Bu'), 0.97 (s, 3H; C(5)-CH3). !3C N M R (CDCI3, 75 MHz): 8 177.1 (-C0 2Me), 135.8, 135.8, 135.7, 134.0, 133.8, 129.4, 127.6, 127.5, 119.1 (C(4)), 68.0, 64.6, 64.5, 51.2, 50.0, 44.4, 41.0, 33.5, 27.0, 23.7, 19.5, 16.5, 13.7. IR (neat film): 3072 (V=C_HX 3022 (V=C-H), 2951, 2883, 2850, 1737 (vc=o), 1590(vc=c), 1470, 1462, 1429, 1391, 1161,1112, 1068 cm"1. DCI-MS (NH 3 ) m/z (rel intensity): 497 ((M + H) + ; 100), 465 ((M - OMe) + ; 5.3), 441 (7.5), 439 ((M - Bu') + ; 56.2), 241 ((M - TBDPS0) + ; 28.1). Exact mass calcd for C 2 5 H 3 1 0 5 S i (M - Bu') + 439.1941, found 439.1944. Anal. Calcd for C 2 9 H4o0 5 Si: C, 70.12; H, 8.12. Found: C, 70.04; H, 8.05. 133 Table 5.4. Results of NOE Experiments for Ketal-ester 165. Proton(s) Irradiated (ppm) Assignment NOE Correlations (ppm) Assignments* 3.27 -CXbMe 7.65-7.70, 7.33-7.44 3.68, 3.36,2.47,2.28-2.38, 1.08, 1.04 -C6H5, H(6), H(10), H(l), C(10)-Me, Bu' 2.47 H(10) 7.65-7.70, 7.33-7.44, 3.68, 3.27, 1.08, 1.04,0.97 -C6H 5 , H(6), Bu', C(10)-Me, C(5)-Me 1.08, 1.04** C(10)-Me, Bu' 7.65-7.70,7.33-7.44, 3.27, 2.28-2.38, 2.47, 1.71-1.85 (part of multiplet), 1.28-1.35 -C6H5, -CO?Me, H(l), H(10), H(2) 0.97 C(5)-Me 3.68,3.36, 3.27, 2.47, 1.71-1.85, 1.08 H(6), -C02Me, H(10), C(10)-Me *Only those protons that can be assigned unambiguously have been recorded. **A11 attempts to irradiate selectively the signals at 1.08 and 1.04 ppm were unsuccessful. Table 5.5. Spectral Data from COSY Spectrum of Ketal-ester 165. 400 MHz ! H NMR Spectrum Signal Positions [S (ppm)] Assign-ment COSY Correlations Signal Positions [8 (ppm)] Assignment 7.65-7.70 -Q3H5 7.33-7.44 -C6H5 7.33-7.44 - C 6 H 5 7.65-7.70 3.68 H(6A) 3.36 H(6B) 3.36 H(6B) 3.68 H(6A) 2.47 H(10) 2.28-2.38, 1.08 H(l), C(10)-Ms 2.28-2.38 H(l) 2.47,1.711.85 (part of multiplet), 1.28-1.35 H(10) H(2A,2B) 1.71-1.85 H(2A), H(3 a,3B) 2.28-2.38,1.28-1.35 H(l), H(2A) 1.28-1.35 H(2B) 2.28-2.38, 1.71-1.85 H(1),H(2B), H(3A,3B) 1.08 C(10)-Me 2.47 H(10) 134 Ketal-alcohol (170) To an ice-cold suspension of lithium aluminum hydride (0.1471 g, 3.876 mmol) in THF (10 mL) was added by cannula an ice-cold solution of ketal-ester 165 (1.9254 g, 3.876 mmol) in THF (30 mL). The grey suspension was stirred at 0 °C for 1 h, then diluted with dry Et20 (30 mL) and quenched cautiously by dropwise addition of water (10 mL). The mixture was stirred at room temperature for 1 h. The organic layer was then separated while the aqueous layer was extracted further with ether (4 x 10 mL). The combined organic extracts were washed with brine (2 x 50 mL), dried over anhydrous MgS0 4 and concentrated to provide a Colorless syrup. Subsequent purification by flash column chromatography (15% acetone-pet. ether) yielded pure ketal-alcohol 170 as a clear, viscous syrup (1.5588 g, 97%). ! H NMR ( C D C 1 3 , 400 MHz): 8 7.63-7.73 (m, 4H; -C&s), 7.34-7.45 (m, 6H; -C6H5), 3.66-3.77 (m, 4H; - O C H 2 C H 2 O - ) , 3.64 (d, J = 10.5 Hz, 1H; H(6A)), 3.60 (d,7 = 10.5 Hz, 1H; H(6B)), 3.39-3.50 (m, 2H; H(9)), 2.02-2.10 (m, 1H), 1.62-1.82 (m, 5H), 1.39-1.50 (m, 1H), 1.09 (s, 9H; BuO, 0.94 (s, 3H; C(5}-CH3), 0.92 (d,7 = 6 Hz, 3H; C(10)-CH3). 13C NMR (CDCI3, 75 MHz): 8 135.9, 135.8, 133.6, 129.6, 127.6, 119.4, 68.2, 67.5, 64.5, 64.1, 50.0,43.4, 36.6, 33.0,27.1,23.0,19.4,15.3,14.3. IR (neat film): 3451 (broad, VO-H), 3072 (V = C -H) , 3049 (V=C_H), 2975, 2961, 2890, 2880, 1590 (vC=c), 1473,1428,1391,1113,1080 cm-1. DCI-MS (NH3) mlz (rel intensity): 469 ((M + H) + ; 32), 213 (44), 199 (100), 195 (48), 181 (16), 165 (11), 151 (28), 135 (24), 121 (16), 105 (14), 99 (76), 86 (19). Exact mass calcd for C 2 8H 4 i0 4 Si [(M + H)4]: 469.2774, found 469.2791. Anal. Calcd for C28H 4 i0 4 Si: C, 71.75; H, 8.60. Found: C, 71.80; H, 8.73. 135 Ketal-iodide (172) O H 5:3 E t 2 0 - C H 3 C N , 0°C I2, PPh 3, imidazole To an ice-cold, colorless solution of ketal-alcohol 170 (1.3929 g, 2.972 mmol), triphenylphosphine (1.1692 g, 4.458 mmol) and imidazole (0.3035 g, 4.458 mmol) in 5:3 diethyl ether-acetonitrile (30 mL) were added iodine crystals (0.9806 g, 3.863 mmol) in several portions over 5 min until a pale yellow endpoint was reached.96 The ice bath was removed and the solution was stirred at room temperature for 5 h. The reaction mixture was partitioned between H2O (50 mL) and Et20 (50 mL). The aqueous layer was extracted with Et20 (50 mL). The combined extracts were washed successively with saturated aqueous NaHS03 (2 x 50 mL), saturated aqueous NaHC03 (1 x 50 mL), and brine (3 x 50 mL) dried over anhydrous MgSO-4. Removal of solvent by rotary evaporation yielded a white, pasty oil. Subsequent purification of the crude product by flash chromatography (10% Et20-pet. ether) yielded pure ketal-iodide 172 as a clear, colorless, viscous oil (1.3736 g, 80%). * H N M R (CDCI3,400 MHz): 8 7.65-7.71 (m, 4H; -CgHs), 7.34-7.44 (m, 6H; -C6H5X 3.73-3.80 (m, 3H; ketal), 3.56-3.66 (m, 3H; ketal, H(6)), 3.44 (dd, J = 9.3, 3.7 Hz, 1H; H(9A)), 3.11 (dd, J =9.3, 7.6 Hz, 1H; H(9B)), 1.94 (unresolved ddd, /=17.5, 8.0', 1.0 Hz, 1H, H(3A)), 1.61-1.77 (m, 4H; H(3B), H(2A), H(10), H(l)), 1.34-1.45 (m, 1H; H(2B)), 1.12 (s, 9H; Bu'), 1.00 (d, / = 6.6 Hz, 3H; C(10)-CH 3), 0.93 (s, 3H; C(5)-CH3) 1 3 C N M R (CDCI3, 75 MHz): 8 135.88, 133.5, 129.5, 127.6, 119.4, 67.9, 64.7, 64.2, 50.1, 48.2, 36.1, 32.9,27.1,23.5,19.4,18.5,13.6. IR (neat film): 3070 (V = C _H), 3052 (V=C_H), 2952, 2885,1590 (vC=c), 1470,1391, 1115,1075 cm' ,-1 136 DCI-MS (NH 3) mlz (rel intensity): 579 ((M + H) + ; 100), 521 (23), 477 (24), 457 (67), 323 (54), 195 (18), 183 (12). Exact mass calcd for C 2 8H 4 oI0 3 Si (M + H ) + : 579.1751, found 579.1766. Ketal-dithiane (173) To a solution of 2-methyl-l,3-dithianev/ (0.88 mL, 0 . 9 9 g, 7 . 4 mmol; CAUTION: STENCH!) in THF (15 mL) at -25 °C was added «-butyllithium (5 .3 mL, 1.55 M in hexane, 8.2 07 mmol), dropwise over 15 min. The colorless solution was stirred at -25 °C for 3 h. A solution of ketal-iodide 172 (2.3765 g, 4.1072 mmol) in THF (50 mL) was cooled to -25 °C and added dropwise to the reaction mixture by cannula over ~10 min. The pale yellow solution was stirred at (-25 ± 5) °C for 12 h after which it was allowed to warm to room temperature and partitioned between H 2 O (50 mL) and E t 2 0 (50 mL). The aqueous layer was extracted further with E t 2 0 (3 x 50 mL). The combined ether extracts were washed successively with H 2 0 (50 mL) and brine (3 x 50 mL), dried over anhydrous MgSC»4, and concentrated under reduced pressure to yield a pale yellow oil. Purification of the crude product by flash chromatography (10% EtOAc-pet. ether) yielded pure ketal-dithiane 173 as a clear, colorless, viscous oil (2.0746 g, 8 6 % ) . 1H N M R ( C D C I 3 , 400 MHz): 8 7 .64-7.73 (m, 4 H ; -CgHs), 7.32-7.41 (m, 6 H ; - C 6 H 5 ) , 3 . 7 4 -3.84 (m, 4 H ; - O C H 2 C H 2 O - ) , 3.65 (d, J = 10.5 Hz, 1 H ; H(6A)), 3.60 (d, J = 1 0 . 5 Hz, 1 H ; H ( 6 B ) ) , 2.67-2.84 (m, 4 H ; - S C H 2 C H 2 C H 2 S - ) , 1.93-2.08 (m, 4 H ; H(10), H ( 3 A ) , H (9)) , 1.83-1.91 (m, 2H; - S C H 2 C H 2 C H 2 S - ) , 1.68-1.80 (m, 3 H ; H(2A), H ( 3 B ) , HQ)), 1.57 (s, 137 3H; H(7)), 1.51-1.64 (m, 1H; H(2B)), 1.08 (s, 9H; Bu'), 1.02 (d, J = 7.3 Hz, 3H; C(10>-CH 3 ) , 0.98 (s, 3H; C(5)-CH 3) !3C N M R (CDC1 3 , 75 MHz): S 135.9, 135.8, 133.9, 133.8, 129.4, 127.5, 119.1, 68.8, 64.5, 50.8, 49.9,49.7,49.3, 34.1, 29.7, 28.1, 27.1, 26.7, 25.2, 20.3, 19.4, 19.3, 14.5. IR (neat film): 3076 ( V = C - H ) , 3045 (V = C _H) , 2960, 2932, 2880, 2850, 1590 (vC=c), 1472, 1428, 1390, 1280, 1112,1082 cm" 1 EIMS m/z (rel intensity): 584 ((M + ; 0.3), 527 (11), 483 (2), 419 (1), 409 (2), 379 (2), 349 (2), 335 (4), 307 (2), 295 (1), 285 (6), 267 (14), 255 (3), 199 (71), 133 (100). Exact mass calcd for C33H4803S2Si: 584.2814, found 584.2818. Silyloxy-ketone (174) To a mixture of ketal-dithiane 173 (1.3063 g, 2.233 mmol) and calcium carbonate (0.5588 g, 5.583 mmol) in THF (15 mL) was added dropwise over 5 min a solution of mercuric perchlorate trihydrate (1.5193 g. 3.349 mmol) in water (4 mL) . 9 9 The reaction mixture was stirred for another 5 min, then diluted with Et 2 0 (80 mL) and poured into water (100 mL). The organic layer was washed further with water (100 mL) and brine (2 x 100 mL), dried over anhydrous MgS04 and concentrated under reduced pressure to yield a viscous, clear, colorless syrup. Subsequent purification by flash column chromatography (30% Et20-pet. ether) provided pure silyloxy-ketone 174 as a clear, colorless syrup (1.0281 g, 93%). 138 1H N M R (CDCI3, 400 MHz): 8 7.62-7.70 (m, 4H; -CfiHs), 7.32-7.42 (m, 6H; -C6H5), 3.74-3.82 (m, 3H; ketal), 3.65-3.72 (m, 1H; ketal), 3.59 (d, / = 10.0 Hz, 1H; H(6A)), 3.55 (d, / = 10.0 Hz, 1H; H(6B)), 2.61-2.71 (m, 1H; H(9A)), 2.05-2.17 (m, 1H; H(9B)), 1.97 (s, 3H; H(7)), 1.59-1.86 (m, 5H), 1.33-1.44 (m, 1H), 1.08 (s, 9H; BuO, 0.97 (s, 3H; C(5)-CH 3 ) , 0.82 (d, J = 5.5 Hz, 3H; C(10)-CH3). 13C N M R (CDCI3, 75 MHz): 8 208.9 (C(8)), 135.8, 133.8, 133.6, 129.6, 127.6, 119.5, 68.2, 64.6, 64.3, 51.1, 50.1,48.0, 32.9, 30.2, 27.0, 23.5, 19.4, 18.0, 13.8. IR (neat fdm): 3072 (V=C_H). 3045 (v=c_H), 2960, 2928, 2881, 2850, 1717 (vc=o), 1590 (vC=c), 1472, 1428, 1361, 1309, 1151, 1113,1076 cm" 1 . DCI-MS (NH 3) m/z (rel intensity): 512 ((M + NH4 + ) + ; 100), 495 ((M + H ) + ; 65), 479 (19), 454 (3), 437 (11), 417 (5), 392 (1), 360 (0.9), 330 (0.6), 274 (0.5). Exact mass calcd for C 3 o H 4 3 0 4 S i [(M + H)+; DCI]: 495.2931, found 495.2939. Anal. Calcd for C 3 o H 4 2 0 4 S i : C, 72.83; H, 8.56. Found:" C, 72.65; H, 8.51. Hydroxy-ketone (178) T B A F (9.7 mL, 1 M in THF, 9.735 mmol) was added to a solution of silyl ketone (174) (0.9633 g, 1.947 mmol) in THF (25 mL) and the resulting pale yellow solution was refluxed for 3 h. The reaction mixture was allowed to cool to room temperature, diluted with diethyl ether (100 mL), washed with water (3 x 50 mL) and brine (3 x 50 mL), dried over anhydrous MgS0 4 , and concentrated under reduced pressure to provide a clear, colorless oil. Purification of the oil 139 by flash column chromatography (60% EtOAc-pet. ether) yielded pure hydroxy-ketone (178) as a clear, viscous, colorless oil (0.4658 g, 93%). * H N M R (CDC13,400 MHz): 8 3.84-3.99 (m, 4H; - O C H 2 C H 2 O - ) , 3.61 (dd, J = 12.4, 2.8 Hz, 1H; simplifies to (d, J = 12.4 Hz) upon addition of D 2 0 ; H(6A)), 3.27 (dd, J = 12.4,10.4 Hz, 1H; simplifies to (d, J = 12.4 Hz) upon addition of D 2 0 ; H(6B)), 2.95 (dd, J = 10.5, 2.8 Hz, 1H; exchanges with D 2 0 ; -OH), 2.67 (dd, J = 17.0, 2.8 Hz, 1H; H(9A)), 2.34 (dd, J = 17.0, 9.0 Hz, 1H; H(9B)), 2.15 (s, 3H; H(7)), 2.02-2.18 (m, 2H; H(10), H(l)), 1.62-1.83 (m, 3H; H(3A), H(3B), H(2A)), 1.38-1.48 (m, 1H; H(2B)), 0.83 (d, / = 6.1 Hz, 3H; C(10)-CH3), 0.80 (s, 3H; C(5)-CH3). IR (neat film) 3533 (broad, V 0 _H) , 2970, 2881, 1713 (vc=oX 1413, 1361, 1324, 1152, 1069, 1043 cm"1. EIMS mlz (rel intensity): 256 ( M + ; 0.2), 241 ((M - C H 3 ) + ; 1.0), 238 ((M - H 2 0 ) + ; 5.7), 225 (3.2), 213 (0.5), 197 (4.3), 99 (100). Exact mass calcd for Ci4H2404 256.1674, found 256.1669. Anal. Calcd for Ci4H 2 4 04: C, 65.60; H, 9.44. Found: C, 65.71; H, 9.49. Table 5.6. Spectral Data from COSY Spectrum of Hydroxy-ketone 178. 400 MHz 1H NMR Spectrum Signal Positions [S (ppm)] Assign-ment COSY Correlations Signal Positions [8 (ppm)] Assignment 3.61 H(6A) 3.27, 2.95 H(6 B), - O H 3.27 H(6B) 3.61,2.95 H ( 6 A ) , - O H 2.95 - O H 3.61, 3.27 H(6A ,6 B) 2.67 H(9A) 2.34, 2.02-2.18 (part of multiplet), 0.83 H(9 B), H(10), C(10)-Me 2.34 H(9B) 2.67,2.02-2.18 (part of multiplet) H(9A), H(10), C(10)-Me 2.02-2.18 H(10), H(l) 2.67, 2.34, 0.83 H(9A ,9 B) C(10)-Me 1.62-1.83 H(3A,3B) H(2A) 1.38-1.48 H(2 B) 1.38-1.48 H(2B) 1.63-1.83 H(3 a ,3B,2 a ) 0.83 C(10)-Me 2.67, 2.34, 2.02-2.18 (part of multiplet) H(9A ,9 B) H(10) Keto-aldehyde (179) To a solution of oxalyl chloride (93 /xL, 0.13 g, 1.1 mmol) in dry CH2CI2 (5.0 mL) at -78 °C was added dropwise over 10 min a solution of dry DMSO (82 / iL, 0.90 g, 1.1 mmol) in CH2CI2 (5.0 m L ) . 1 0 0 The clear, colorless solution was stirred at -78 °C for 30 min after which a solution of the hydroxy-ketone 178 (0.2265 g, 0.8835 mmol) in CH2CI2 (5.0 mL) was added 141 dropwise by cannula over 5 min. The reaction mixture was stirred at -78 °C for a further hour. Triethylamine (0.62 mL, 0.45 g, 4.4 mmol) was added and the solution was allowed to warm to room temperature over 1 h, and was stirred subsequently at room temperature for 4 h. The reaction mixture was diluted with CH2CI2 (-100 mL), washed with ice-cold 0.5 M HC1 (2 x 25 mL), water (2 x 50 mL) and brine (3 x 50 mL), dried over anhydrous MgSC»4 and concentrated to provide the crude product as a pale yellow oil. Purification of the oil by flash chromatography (50% Et20-pet. ether) provided pure keto-aldehyde 179 as a clear, colorless oil (0.2038 g, 91%) [N.B. Due to the air sensitivity of 179, this compound was stored at -10 °C under argon]. 1H N M R (CDCI3, 400 MHz): 5 9.72 (s, 1H; -CHO), 3.68^1.92 (m, 4H; -OCH2CH2O-), 2.51 (ddd, J = 19.0, 10.5, 3.1 Hz, 1H; H(9A)), 1.75-2.15 (m, 6H; H(10), H(9B), H(l), H(3A), (H(3B), (H(2A)), 2.06 (s, 3H; (H(7))), 1.36-1.50 (m, 1H; H(2A)), 1.07 (s, 3H; C(5)-CH3), 0.89 (d, / = 6.5 Hz, 3H; C(10)-CH3). IR (neat film): 2970, 2885, 2735 ( V C _ H , aldehyde), 1715 (vc=o), 1469, 1370, 1160, 1058 cm"1. EIMS m/z (rel intensity): 254 ( M + ; 0.5), 239 ((M - C H 3 ) + ; 0.3), 225 (0.2), 222 ((M - C H O ) + ; 0.5), 196 ((M - H 2C=C(OH)CH 3) + ; 0.9 (McLafferty)), 181 (0.8), 99 (100). Exact mass calcd for C14H22O4 254.1518, found 254.1515. To a solution of keto-aldehyde 179 (0.1931 g, 0.7592 mmol) in spectro grade methanol (6.5 mL) was added, in one portion, a 10% aqueous potassium hydroxide solution (1.3 mL, 130 142 mg, 2.3 mmol). The reaction mixture was stirred at room temperature under argon for 2 h after which it was neutralized by addition of 1 M H C 1 (-2.5 mL). The mixture was extracted with diethyl ether (3 x 25 mL). The combined extracts were washed with brine (2 x 50 mL), dried over anhydrous MgSC>4, and evaporated to yield the crude aldol 180 as a viscous, colorless syrup (0.1831 g) that was used in the subsequent reaction without further purification; IR (neat film): 3519 (br; V 0 _ H ) , 2962, 2896, 1697 (vc=o), 1461, 1380, 1344, 1170, 1129, 1073, 1023, 950 cm"1. To an ice-cold solution of aldol 180 (0.1831 g, 0.7199 mmol), triethylamine (180 ph, 0.109 g, 1.08 mmol), and DMAP (0.0879 g, 0.7199 mmol) in dry CH2CI2 (8 mL) was added methanesulfonyl chloride (84 /zL, 0.12 g, 1.08 mmol). The cloudy, straw yellow solution was stirred at 0 °C for 1.5 h after which DBU (215 fiL, 0.219 g, 1.44 mmol), pre-purified by passage down a column of basic alumina, was added and the solution was allowed to warm to room temperature. The clear, pale yellow solution was stirred for 2.5 h and then poured into a 1:1 diethyl ether-water mixture (50 mL). The aqueous layer was extracted further with diethyl ether (2 x 25 mL). Combined extracts were washed with water (3 x 25 mL), saturated aqueous NaHC03 (3 x 25 mL), and brine (3 x 25 mL), dried over anhydrous MgS04, and concentrated to a pale yellow oil. Subsequent purification of the oil by flash column chromatography (50% Et20—pet. ether) yielded pure ketal-enone 140 as a colorless oil (0.1472 g, 82% from the keto-aldehyde 179); [a]g -15.7 (c 0.896, CHCI3). * H N M R ( C D C I 3 , 400 MHz): S 6.40 (d, J = 12 .0 Hz, 1 H ; H(6)), 5.91 (d, J = 12.0 Hz, 1 H ; H(7)), 3.86^1.04 (m, 4 H ; - O C H 2 C H 2 O - ) , 2.92 (dd, J = 13.0, 6.5 Hz, 1 H ; H(9/3)), 2.29 (dd, J = 13.0,4.6 Hz, 1 H ; H(9a)), 1.89-2.06 (m, 3 H ; H (10 ) , H(l), and H(3A)), 1.72-1.86 (m, 2 H ; H (2A) and H(3B)), 1.36-1.46 (m, 1 H ; H ( 2 B ) ) , 1.12 (s, 3 H ; C(5)-CHJX 1-01 (d, J = 6.4 Hz, 3 H ; C ( 1 0 ) - C H 3 ) . 143 13C N M R (CDCI3, 75 MHz): 8 203.4 (C=0), 148.4 (C(6)), 130.5 (C(7)), 119.3 (C(4)), 65.5 (—OCH2CH2O-), 64.0 (-OCH2CH2O-), 51.8 (C(9)), 49.9 (C(l)), 31.6 (C(10)), 31.1 (C(3)), 25.2 (C(2)), 20.7 (C(10) -£H 3 ) , 15.9 (C(5)-CH3). IR (neat film): 2959, 2878,1672 (vc=o), 1626 (shoulder; vc=c), 1460, 1439,1390, 1344, 1165 (VC-O, asym), 1061 (vC_o, Sym), 950, 756 c n r l EIMS m/z (rel intensity): 236 ( M + ; 0.6), 193 (0.2), 176 (0.2), 165 (0.3), 153 (0.4), 147 (0.3), 135 (0.4), 126 (0.9), 107 (1), 99 (100) Exact mass calcd for C14H20O3: 236.1412, found 236.1410. Anal. Calcd for C14H20O3: C, 71.16; H, 8.53. Found: C, 71.05; H, 8.48. Table 5.7. Results of NOE Experiments for Ketal-enone 140. Proton Irradiated (ppm) Assignment NOE Correlations (ppm) Assignments* 2.92 H(90) 2.29, 1.12, 1.89-2.06 (part of multiplet) H(9a), C(5)-Me H(10) 2.29 H(9a) 2.92, 1.01 H(9/3), C(10)-Me 1.12 C(5)-Me 2.92, 5.91 1.89-2.06 (part of multiplet), 1.72-1.86 (part of multiplet) H(9£), H(7) 1.01 C(10)-Me 2.29,1.89-2.06 (part of multi-plet) H(9a), H(10) *Only those protons that can be assigned unambiguously have been recorded. Table 5.8. Spectral Data from COSY Spectrum of Ketal-enone 140. 400 MHz lH NMR Spectrum Signal Positions [S (ppm)] Assign-ment COSY Correlations Signal Positions [8 (ppm)] Assignment 6.40 H(6) 5.91 H(7) 5.91 H(7). 6.40 H(6) 2.92 H(90) 2.29,1.89-2.06 (part of multiplet) H(9a), H(10) 2.29 H(9a) 2.92, 1.89-2.06 (part of multiplet) H(9p), H(10) 1.89-2.06 H(10), H(l), H(3A) 2.92, 2.29, 1.72-1.86, 1.36-1.46, 1.01 H(9a,9£) , H(2 a ,2B,3B) C(10)-Me 1.72-1.86 H(2A,3B) 1.89-2.06 (part of multiplet), 1.36-1.46 H(1),H(2B), H(3A) 1.36-1.46 H(2B) 1.89-2.06 (part of multiplet), 1.72-1.86 H(1),H(2A), H(3 a ,3B) 1.01 C(10)-Me 1.89-2.06 (part of multiplet) H(10) • Table 5.9. Spectral Data from HETCOR Spectrum of Ketal-enone 140 75 MHz 1 3 C NMR Spectrum Assign- HETCOR Correlations Assign-Signal Positions [SQ (ppm)] ment Signal Positions [5H (ppm)] ment 148.4 C(6) 6.40 H(6) 130.5 C(7) 5.91 H(7) 65.5, 64.0 ketal 3.86-4.04 ketal 51.8 C(9) 2.92,2.29 H(9) 49.9 C(l) 1.89-2.09 (part of multiplet) H(l) 31.6 C(10) 1.89-2.09 (part of multiplet) H(10) 31.1 C(3) 1.89-2.09 (part of multiplet), 1.72-1.86 (part of multiplet) H(3) 25.2 C(2) 1.72-1.86 (part of multiplet), 1.36-1.46 H(2) 20.7 C(10)-Me 1.01 C(10)-Me 15.9 C(5)-Me 1.12 C(5)-Me 145 Bicyclic Keto-enone (181) H \ H \ '140 O 1 MHC1 acetone 0 O 181 Ketal-enone 140 (53.6 mg, 0.227 mmol) was dissolved in acetone (3.0 mL) and 1 M HC1 (3.0 mL) was added. The colorless solution was stirred at room temperature for 3 h after which it was diluted with water (10 mL) and extracted with diethyl ether (3 x 25 mL). The combined extracts were washed with water (1 x 50 mL), saturated NaHC03 solution (1 x 50 mL) and brine (3 x 50 mL), dried over anhydrous MgSC>4 and concentrated under reduced pressure to afford a colorless oil. Subsequent purification of the oil by flash chromatography (50% Et20-pet. ether) yielded pure keto-enone 181 as a white, crystalline solid (38.7 mg, 89%); mp = 71.5-72.5 °C. * H N M R (CDC1 3, 400 MHz): 8 6.81 (d, / = 12.7 Hz, 1H; H(6)), 5.98 (dd, J = 12.7, 1.4 Hz, 1H; H(7)), 3.03 (dd, J = 12.8, 7.8 Hz, 1H; H(9A)), 2.45-2.58 (m, 1H; H(3A)), 2.33 (ddd, / = 13.0, 3.5, 1.4 Hz, 1H; H(9B)), 2.02-2.24 (m, 3H; H(3B), H(2A), H(10)), 1.82-1.91 (m, 1H; H(l)), 1.55-1.66 (m, 1H; H(2B)), 1.14 (s, 3H; C(5)-CH.3), 1-12 (d, / = 6.8 Hz, 3H; C(10)-CM3). 1 3 C N M R (CDCI3, 75 MHz): 8 217.2 (C(3)), 202.3 (C(8)), 147.2 (C(6)), 131.6 (C(7)), 54.6 51.4, 50.7, 35.7, 31.0,24.3,20.3,15.8. IR (neat film): 2965, 2925, 2860, 2742, 2672, 1742 (vC=o, saturated ketone), 1672 (yC=o, unsaturated ketone), 1458 cm - 1 . EIMS m/z (rel intensity): 192 ( M + ; 100), 177 ((M - C H 3 ) + ; 4.8), 164 (48.3), 159 (7.9). Exact mass calcd for C12H16O2: 192.1150, found 192.1148. 146 Bicyclic Hydroxy-enone (182) To a solution of keto-enone 181 (22.1 mg, 115 //mol) in absolute ethanol (1.0 mL) at -10 °C was added solid sodium borohydride (1.2 mg, 31 fimol) in one portion. 1 0 3 The resulting clear, colorless solution was stirred at -10 °C for 10 min, and then neutralized by addition of 1 M HC1 (3 drops). The reaction mixture was diluted with diethyl ether (50 mL) and poured into water (25 mL). The aqueous phase was extracted further with diethyl ether (2x15 mL). The combined extracts were washed with saturated aqueous NaHCC»3 (1 x 25 mL) and brine (1 x 50 mL), dried over anhydrous MgSC»4, and concentrated to yield a white, sticky foam. Subsequent purification by flash column chromatography (90% diethyl ether-pet. ether) yielded the desired hydroxy-enone 182 (18.9 mg; 85%) as a clear, colorless film. 1H N M R (CDCI 3 , 400 MHz): 8 6.62 (d, J = 11.6 Hz, 1H; H(6)), 5.91 (dd, J = 11.6, 1.5 Hz, 1H; H(7)), 3.58-3.64 (m, 1H; H(4)), 3.06 (dd, J =12.4, 7.8 Hz, 1H; H(9A)), 2.25 (ddd, / = 12.7, 3.5, 1.4 Hz, 1H; H(9B)), 1.99-2.09 (m, 1H; H(3A)), 1.82-1.98 (m, 2H; H(10), H(2A)), 1.62 (bs, 1H; exchanges with D 2 0 ; -OH), 1.34-1.58 (m, 3H; H(l), H(3B), H(2B)), 1.03 (s, 3H; C(5)-CH3), 1.00 (d, / = 6.7 Hz, 3H; C(10)-CH3). 13C N M R (CDCI3, 75 MHz): 8 202.9 (C(8)), 151.0 (C(6)), 130.1 (C(7)), 50.7, 49.8, 49.4, 32.3,26.70,25.7,20.7,10.5. IR (neat film): 3363 (broad, V0_H), 2956, 2925, 2873, 1687 (vc=o), 1458, 1376, 1262, 1142, 1107,1072,1025 cm- 1 . 147 EIMS m/z (rel intensity): 194 ( M + ; 35.0), 179 ((M - C H 3 ) + ; 6.5), 161 (7.0), 150 (100), 135 (35.0). Exact mass calcd for C12H18O2: 194.1307, found 194.1311. Results of N O E experiment: Irradiation of the signal at 8 3.58-3.64 [H(4)] resulted in enhancement of signal intensities at 6.62 [H(6)], 1.99-2.09 [H(3A)], 1.82-1.98, 1.62 [-OH], and 1.34-1.58 ppm. Table 5.10. Spectral Data from COSY S pectrum of Hydroxy-enone 182. 400 MHz J H NMR Spectrum Signal Positions [8 (ppm)] Assign-ment COSY Correlations Signal Positions [8 (ppm)] Assignment 6.62 H(6) 5.91 H(7) 5.91 H(7) 6.62, 2.25 H(6), H(9B) 3.58-3.64 H(4) 1.99-2.09, 1.62, 1.34-1.58 (part of multiplet) H ( 3 A ) , - O H , H(3B) 3.06 H(9A) 2.25,1.82-1.98 (part of multiplet) H(9B), H(10) 2.25 H(9B) 5.91, 3.06, 1.82-1.98 (part of multiplet) H(7), H(9A), H(10) 1.99-2.09 H(3A) 3.58-3.64 1.82-1.98 (part of multiplet) 1.34-1.58 (part of multiplet) H(4), H(2 A , 2 B , 3 B ) 1.82-1.98 H(10), H(2A) 3.06,2.25,1.99-2.09 1.34-1.58 H(9 A , 9 B , 1) H(2 B , 3A, 3B) 1.62 - O H 3.58-3.64 H(4) 1.34-1.58 H(l), H(2B), H(3B) 3.58-3.64,1.99-2.09 1.82-1.98 H(4),H(3A) H(10), H(2A) 1.00 C(10)-Me 1.82-1.98 (part of multiplet) H(10) 148 Hydroxy-ketone (123) To a solution of hydroxy-enone (182) (12.5 mg, 63.0 jumol) in absolute ethanol (1.5 mL) was added 10% palladium on charcoal (5 mg). The mixture was stirred under an atmosphere of hydrogen (ambient pressure) for 3 h, then diluted with Et20 (50 mL) and filtered through a pad of Celite®. The Celite® pad was washed further with Et20 (50 mL). The filtrate was concentrated to yield a clear, colorless film. Purification by flash column chromatography (90% Et20—pet. ether) yielded pure hydroxy-ketone (123) as a clear, colorless film (11.6 mg; 95%) * H N M R (CDCI3, 400 MHz): 8 3.60-3.66 (m, 1H; H(4)), 3.10 (dd, J = 12.5, 7.5 Hz, 1H), 2.25 (ddd, J - 12.5, 3.0, 1 Hz, 1H), 1.72-2.10 (m, 5H), 1.32-1.57 (m, 4H), 1.03 (s, 3H; C(5)-CH 3), 0.96 (d, J = 7.0 Hz, 3H; C(10)-CH3). 1 3 C N M R (CDCI3, 75 MHz): 8 213.0 (C(8)), 79.8 (C(4)), 50.7, 49.5, 45.4, 41.5, 40.9, 35.6, 30.1,23.3,13.2,10.5. IR (neat film): 3400 (broad, VO-H)> 2970, 2885,1695 (vc=o), 1477, 1392, 1112 cnr 1 . EIMS mlz (rel intensity): 196 (M+; 20.3), 181 (10.5), 178 (2.5), 99 (100). Exact mass calcd for C i 2 H 2 o 0 2 196.1463, found 196.1468. Anal. Calcd for C12H20O2: C, 73.43; H, 10.27. Found: C, 73.50; H, 10.31. 149 Ketal-ester (184): Stereoselective Alkylation of Ketal-ester (164b) with Allyl Bromide «-Butyllithium (5.8 mL, 1.55 M in hexane, 8.9 mmol) was added dropwise over 5 min to a solution of diisopropylamine (1.3 mL, 0.90 g, 8.9 mmol) in T H F (15 mL) at 0 °C. The solution was stirred at 0 °C for 30 min and then cooled to -78 °C. Ketal-ester 164b (3.3224 g, 6.883 mmol), dissolved in THF (25 mL), was added and the reaction mixture was stirred at -78 °C for 45 min. Allyl bromide (0.77 mL, 1.1 g, 8.9 mmol) was then added and the mixture was stirred at -78 °C for a further 2 h before being allowed to warm to room temperature over 15 h. The solution was partitioned between ether (50 mL) and water (50 mL). The aqueous layer was further extracted with ether (2 x 50 mL) and the combined extracts were washed with brine (3 x 100 mL), dried over anhydrous MgS04, and concentrated under reduced pressure to provide a pale yellow oil. Purification of the crude product by flash chromatography (10% EtOAc-pet. ether) yielded the ketal-ester 184 (3.4002 g; 95%) as a viscous, colorless oil. ! H N M R (CDC1 3, 400 M H z ) : 8 7.64-7.70 (m, 4 H ; -C6H5), 7.30-7.42 (m, 6 H ; -C6H5) , 5.09-5.20 (m, 1H; H(8)), 4.90-5.00 (m, 2 H ; H(7)), 3.79-3.91 (m, 4 H ; - O C H 2 C H 2 O - ) , 3.69 (d, J = 8.0 Hz, 1H; H(6A)), 3.34 (d, J = 8.0 Hz, 1H; H(6B)), 3.20 (s, 3 H ; -C02Me), 2.46 (ddd, / = 9.5, 9.5, 3.0 Hz, 1H; H(10)), 2.27-2.36 (m, 2 H ; H(l), H(9A)), 2.09-2.19 (m, 1H; H(9B)), 1.75-1.84 (m, 3H; H(3A), H(3B), H(2A)), 1.31-1.41 (m, 1H; H(2A)), 1.04 (s, 9 H ; BuO, 0.99 (s, 3H; C(5)-CH 3). 13C N M R (CDCI3, 75 M H z ) : 8 175.4 ( -C0 2 Me), 135.8, 135.7, 135.2, 134.0, 133.8, 122.4, 127.6, 119.0,116.6, 67.9, 64.7 64.5, 50.8, 50.0, 47.3, 43.6, 35.4, 33.4, 27.0, 24.02, 19.4, 13.6. 164b 184 150 IR (neat film): 3073 (v=c_H), 3050 ( V = C _ H ) , 2948, 2858, 1735 (vc=o), 1642 (vc=c), 1590 (vC=c), 1472, 1429, 1391, 1371,1318, 1112cm-l. EIMS m/z (rel intensity): 522 ( M + , 1.0), 491 (4.8), 465 (100), 435 (8.9), 421 (29.0), 409 (8.4), 387 (8.5). Exact mass calcd for C 3 i H 4 2 0 5 S i 522.2801, found 522.2807. Anal. Calcd for C 3 i H 4 2 0 5 S i : C, 71.23; H, 8.10. Found: C, 71.30; H, 8.03. Table 5.11. Results of NOE Experiments for Ketal-ester 184. Proton(s) Irradiated (ppm) Assignment NOE Correlations (ppm) Assignments* 0.99, 1.04** C(5)-Me and Bu' 3.69, 3.34, 3.20 2.46, 1.75-L84 (part of multi-plet), 1.31-1.41 H(6 A , 6B), - C 0 2 M e , H(10), H(2B) 2.46 H(10) 5.09-5.20, 3.34, 3.20, 2.27-2.36,2.09-2.19,0.99-H ( 8 , 6 B , 9 A , 9B, 1),' - C 0 2 M e , C(5)-Me 3.20 - C 0 2 M e 2.46, 2.27-2.36, 2.09-2.19, 0.99 H(10, 1,9A, 9B), C(5)-Me 3.69 H(6A) 7.64-7.70, 7.30-7.42, 3.34, 2.46, 0.99 -Ph, H(6B), C(5)-Me 3.34 H(6B) 7.64-7.70, 7.30-7.42, 3.69, 2.46, 0.99 -Ph, H(6A), H(10), C(5)-Me *Only those protons that can be assigned unambiguously have been recorded. A l l attempts to irradiate selectively the singlets at 0.99 and 1.04 were unsuccessful. 151 Table 5.12. Spectral Data from COSY Spectrum of Ketal-ester 184 400 MHz *H NMR Spectrum Assign- COSY Correlations Assignment Signal Positions [8 (ppm)] ment Signal Positions [8 (ppm)] 7.64-7.70 -Ph 7.30-7.42 -Ph 7.30-7.42 -Ph 7.64-7.70 -Ph 5.09-5.20 H(8) 4.90-5.00,2.27-2.36 (part of multiplet), 2.09-2.19 H(7),H(9A), H(9B) 4.90-5.00 H(7) 5.09-5.20 H(8) 3.69 H(6A) 3.34 H(6B) 3.34 H(6B) 3.69 H(6A) 2.46 H(10) 2.27-2.36, 2.09-2.19 H(1,9 A , 9B) 2.27-2.36 H(l, 9A) 2.46, 2.09-2.19, 1.75-1.84 (part of multiplet), 1.31-1.41 HQ0, 9B), H(2A , 2B) 2.09-2.19 H(9B) 2.46, 2.27-2.36 (part of multiplet) H(10), H(9A) 1.75-1.84 H(3 a ,3B) 2.27-2.36 (part of multiplet), H(l), H(2A) 1.31-1.41 H(2B) 1.31-1.41 H(2B) 2.27-2.36 (part of multiplet), 1.75-1.84 H(l), H(2A), H(3A , 3B) Ketal-alcohol (185) To a suspension of lithium aluminum hydride (0.3703 g, 9.757 mmol) in THF (10 mL) at 0 °C was added the ester 184 (3.4002 g, 6.504 mmol) in THF (50 mL). The reaction was allowed to proceed at 0 °C for 2 h before being quenched by cautious, dropwise addition of water (-10 mL). The two-phase mixture was stirred for a further 30 min, and the aqueous phase was then extracted with ether (5 x 25 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous MgS04, and concentrated under reduced pressure to a viscous, colorless oil. Purification of this crude product by flash chromatography (20% EtOAc-pet. ether) yielded the ketal-alcohol 185 (3.0497 g; 95%) as a colorless syrup. 1H N M R (CDC1 3, 400 MHz): S 7.62-7.72 (m, 4H; -C6H 5 ) , 7.32-7.42 (m, 6H; -C6H5), 5.77-5.89 (m, 1H; H(8)), 4.98-5.09 (m, 2H; H(7)), 3.57-3.74 (m, 6H), 3.50-3.57 (m, 1H; simplifies to 3.52 (dd, / = 11.5, 4.0 Hz) upon addition of D 2 0 ; C(10)-CH2OH), 3.42-3.50 (m, 1H), 2.18-2.32 (m, 2H), 1.97-2.07 (m, 1H), 1.88 (bs, 1H; exchanges with D 2 0 ; -OH), 1.61-1.83 (m, 4H), 1.38-1.48 (m, 1H), 1.09 (s, 9H; Bu'), 0.95 (s, 3H; C(5)-CH3). IR (neat film): 3479 (broad, V 0 _ H ) , 3072 ( V = C - H ) . 3050 ( V = C _ H ) , 2956, 2870, 1639 (vc=c), 1590 (vc=c), 1472, 1428, 1392, 1365, 1318, 1190, 1112, 1085 cm"1. EIMS m/z (rel intensity): 494 (M+, 1.1), 479 (0.2), 465 (1.2), 437 (69.9), 409 (10.9), 393 (5.7), 375 (16.4). Exact mass calcd for C3fjH4204Si 494.2852, found 494.2844. Anal. Calcd for C3oH 4 2 0 4 Si: C, 72.83; H, 8.56. Found: C, 72.87; H, 8.65. Ketal-mesylate (186) To a solution of alcohol 185 (2.2749 g, 4.598 mmol) in C H 2 C 1 2 (80 mL) at 0 °C was added D M A P (0.2808 g, 2.299 mmol), triethylamine (0.77 mL, 0.56 g, 5.5 mmol), and methanesulfonyl chloride (0.43 mL, 0.63 g, 5.5 mmol). The colorless solution was stirred at 0 153 °C for 2.5 h, then diluted with CH2C I2 (50 mL), washed with water (1 x 100 mL), ice-cold 0.1 M HC1 (2 x 100 mL), water (3 x 100 mL), and brine (3 x 100 mL), and dried over anhydrous MgS04. Concentration of the organic layer under reduced pressure yielded chromatographically pure ketal-mesylate 186 (2.5584 g; 97%) that could be used in the subsequent reaction without further purification. For characterization purposes, a small quantity of the crude ketal-mesylate 186 (-20 mg) was purified by radial chromatography (20% EtOAc-pet. ether). ! H N M R ( C D C I 3 , 400 MHz): 8 7.61-7.68 (m, 4H; -CgHs), 7.34-7.42 (m, 6H; - C d i s ) , 5.70-5.82 (m, 1H; H(8)), 5.03-5.12 (m, 2H; H(7)), 4.21 (dd, / = 8.0, 4.0 Hz, 1H; - C H A H B O M s ) , 4.07 (dd, J = 8.0, 4.0 Hz, 1H; - C H A H B O M S ) , 3.63-3.81 (m, 4H; - O C H 2 C H 2 O - ) , 3.60 (d, J = 10.5 Hz, 1H; H(6A)), 3.55 (d, / = 10.5 Hz, 1H; H(6B)), 2.78 (s, 3H; -SCbMe). 2.37 (ddd, J = 13.4, 6.0, 0.9 Hz, 1H; H(9A)), 2.22-2.30 (m, 1H; H(3A)), 1.93-2.09 (m, 2H; H(10), H(9B)), 1.62-1.79 (m, 3H; H(2A), H(3B), H(l)), 1.42-1.52 (m, 1H; H(2B)), 1.05 (s, 9H; Bu'), 0.99 (s, 3H; C(5)-CH3). 13C N M R (CDCI3,100 MHz): S 135.8,135.6,113.5, 113.5,129.6,128.0,127.7, 127.6,127.4, 118.7, 117.2, 71.2, 68.7, 64.3, 64.1, 49.9, 42.5, 38.1, 36.5, 33.0, 32.1, 27.0, 22.6, 19.3, 14.0. IR (neat film): 3072 ( V = C - H ) , 3050 ( V = C _ H ) - 2957, 2884, 2858, 1640 (vc=c), 1590 (vc=c), 1472, 1428, 1360, 1177,1112 cm-1. EIMS m/z (rel intensity): 572 (M+, 0.1), 557 (0.1), 515 (8.5), 493 (5.4), 471 (1.4), 419(16.4). Exact mass calcd for C3iH44C»6SSi 572.2628, found 572.2619. 154 Ketal-alkene (187): Reduction of Ketal-mesylate 186 OMs To a solution of mesylate 186 (2.5560 g, 4.462 mmol) in THF (50 mL) at 0 °C was added lithium triethylborohydride (SuperHydride®; 9.8 mL, 1.0 M in THF, 9.8 mmol). 1 0 4 The clear, colorless solution was stirred at 0 °C for 5 min and at room temperature for 18 h. The cloudy reaction mixture was cooled to 0 °C, at which 3 M NaOH (2.0 mL) and 30% hydrogen peroxide (2.0 mL) were added successively. The solution was stirred at room temperature for 1 h, during which a white precipitate formed, and then partitioned between Et20 (50 mL) and H2O (50 mL). The aqueous layer was extracted once more with Et20 (50 mL). The combined extracts were washed with H 2 0 (3 x 50 mL) and brine (3 x 50 mL), dried over anhydrous MgSC»4 and concentrated under reduced pressure to provide a colorless oil. Subsequent purification of the oil by flash chromatography (5% EtOAc-pet. ether) yield pure ketal-alkene 187 as a clear, colorless oil (1.9033 g, 89%). * H N M R ( C D C I 3 , 4 0 0 MHz): 8 7.64-7.73 (m, 4H; - C 6 H 5 ) , 7.34-7.46 (m, 6H; -Cdfc) , 5.18-5.30 (m, 1H; H(8)), 4.93-5.00 (m, 2H; H(7)), 3.71-3.83 (m, 4H; - O C 2 C H 2 0 - ) , 3.65 (d, J = 9.0 Hz, 1H; H(6A)), 3.58 (d, J = 9.0 Hz, 1H; H(6B)), 2.19-2.26 (m, 1H), 1.50-1.85 (m, 6H), 1.32-1.42 (m, 1H), 1.05 (m, 9H; Bu'), 0.98 (s, 3H; C(5)-CH3), 0.82 (d, J = 6.6 Hz, 3H; C(10)-CH3) « C N M R ( C D C I 3 , 1 0 0 MHz): 8 135.8,135.7, 134.0,133.8, 129.4, 127.5, 123.1, 119.7, 67.9, 64.6, 64.3, 50.1,48.0,45.4, 38.3, 33.6, 33.4,27.0,25.5,24.4,23.6,21.6,19.4,18.0,14.0. IR (neat film): 3072 ( V = C _ H ) , 3050 ( V = C _ H ) , 2959, 2880, 1640 (vC=c), 1590 (vr>c). 1472, 1428, 1113 cm-1. 155 EIMS m/z (rel intensity): 478 ( M + ; 0.4), 437 (0.3), 421 ((M - BuO + ; 54.5), 391 (44.9), 377 (22.5), 343 (4.1), 161 (100). Exact mass calcd for C30H42O3S1 478.2903, found 478.2901. Silyloxy-ketone (196) A suspension of palladium(II) chloride (0.1282 g, 0.7228 mmol), copper© chloride (0.3582 g, 0.361 mmol) in 7:1 D M F - H 2 O (10 mL) was stirred under oxygen atmosphere for 2 h . 1 0 5 To this green-brown suspension was added a solution of the terminal alkene 187 (1.7303 g; 3.6142 mmol) in 9:1 D M F - H 2 O (40 mL). The mixture was stirred under oxygen for 18 h and filtered through a pad of Celite.® The Celite® pad was washed with E t 2 0 (-50 mL). The filtrate was extracted with Et20 (3 x 50 mL). The combined extracts were washed with NaHC03 (2 x 50 mL), H 2 O (2 x 50 mL), and brine (3 x 50 mL), dried over anhydrous MgSC>4 and concentrated to provide the crude product as a golden-yellow oil. Subsequent purification by flash chromatography (20% EtOAc-pet. ether) yielded pure silyloxy-ketone 196 as a clear, colorless oil (1.5412 g, 86%). *H N M R ( C D C I 3 , 4 0 0 MHz): 8 7.62-7.71 (m, 4 H ; - C 6 H 5 ) , 7.32-7.42 (m, 6 H ; - C 6 H 5 ) , 3.72-3.84 (m, 4 H ; - O C H 2 C H 2 O - ) , 3.60 (d, / = 10 .0 Hz, 1 H ; H(6A)), 3.55 (d,7 = 10 .0 Hz, 1 H ; H ( 6 B ) ) , 2.52-2.62 (m, 1 H ; H(9A)), 2.06-2.16 (m, 1 H ; H(9B)), 2.09 (s, 3 H ; H(7)), 1.62-156 1.92 (m, 5H), 1.20-1.34 (m, 1H), 1.07 (s, 9H; Bu'), 0.97 (s, 3H; C(5)-CH 3), 0.82 (d, J = 8.0 Hz, 3H; C(10)-CH3). !3C N M R (CDCI3,100 MHz): 6 209.0 (C(8)), 135.8, 133.8, 133.6, 129.6, 127.6, 119.6, 68.2, 64.6, 64.3, 51.1, 50.1, 48.1, 32.9, 30.3, 27.0, 23.6, 19.4, 18.1, 13.8. IR (neat film): 3070 ( V = C _ H ) , 3050 ( V = C _ H ) , 2958, 2882, 1716 (vC=o). 1472, 1428, 1361, 1153,1112 cm- 1. DCI-MS (NH3) mlz (rel intensity): 495 ((M + H) + ; 100), 494 (M+; 11.8), 477 (58.3), 437 ((M - B u ' ) + ; 73.8), 433 (23.9), 417 (11.4), 375 (11.4). Exact mass calcd for C26H 3 3 0 4 Si (M - r-Bu)+ 437.2148, found 437.2145. Anal. Calcd for C 3 oH 4 2 04Si : C, 72.83; H, 8.56. Found: C, 72.62; H, 8.56. Hydroxy-ketone (197) T B A F (37.0 mL, 1 M in THF, 37.1 mmol) was added to a solution of silyl ketone (196) (1.8855 g, 3.710 mmol) in THF (35 mL) and the resulting pale yellow solution was refluxed for 5 h. The reaction mixture was allowed to cool to room temperature, diluted with diethyl ether (150 mL), washed with water (3 x 50 mL) and brine (3 x 50 mL), dried over anhydrous MgS0 4 , and concentrated under reduced pressure to provide a clear, colorless oil. Purification of the oil by flash column chromatography (60% EtOAc-pet. ether) yielded pure hydroxy-ketone (197) as a clear, viscous, colorless oil (0.9251 g, 95%). 157 ! H N M R (CDCI3,400 MHz): S 3.84-4.01 (m, 4H; -OCH2CH2O-), 3.60 (dd, J = 12.7, 3.0 Hz, 1H; simplifies to (d, J = 12.7 Hz) upon addition of D 2 0 ; H(6A)), 3.38 (dd, / = 12.7, 9.8 Hz, 1H; simplifies to (d, J = 12.7 Hz) upon addition of D 2 0 ; H(6B)), 2.90 (dd, J = 9.8, 3.0 Hz, 1H; exchanges with D 2 0 ; -OH), 2.51 (dd, / = 16.0, 1.5 Hz, 1H; H(9A)), 2.21 (dd, J = 16.0, 9.0 Hz, 1H; H(9B)), 2.10 (s, 3H; H(7)), 2.00-2.15 (m, 2H), 1.58-1.85 (m, 3H), 1.26-1.37 (m, 1H), 0.97 (d, / = 6.5 Hz, 3H; C(10)-CH3), 0.84 (s, 3H; C(5)-CH3). 13C N M R (CDCI3,100 MHz): 5 208.6 (C(8)), 120.8 (C(4)), 66.1, 64.4, 63.2, 49.4,48.8, 43.3, 31.6, 30.9, 30.4, 24.2,18.8,13.4. IR (neat film): 3534 (broad, V 0 - H X 2969, 2882, 1713 (vc=o), 1467, 1412, 1151, 1068, 1043 cm"1. EIMS m/z (rel intensity): 256 (M+; 0.1), 238 ((M - H20)+; 3.4), 225 (1.3), 213 (0.8), 197 (3.4), 99 (100). Exact mass calcd for C i 4 H 2 4 0 4 256.1674, found 256.1677. Anal. Calcd for C i 4 H 2 4 0 4 : C, 65.60; H, 9.44. Found: C, 65.69; H, 9.52. Keto-aldehyde (198) To a solution of oxalyl chloride (0.27 mL, 0.39 g, 3.1 mmol) in dry C H 2 C 1 2 (5.0 mL) at -78 °C was added dropwise over 10 min a solution of dry DMSO (0.24 mL, 0.26 g, 3.4 mmol) in C H 2 C 1 2 (5.0 m L ) . 1 0 0 The clear, colorless solution was stirred at -78 °C for 30 min after which a solution of the hydroxy-ketone 197 (0.6646 g, 2.5926 mmol) in C H 2 C 1 2 (5.0 mL) was added dropwise by cannula over 5 min. The reaction mixture was stirred at -78 °C for a further 158 hour. Triethylamine (1.8 mL, 1.3 g, 13 mmol) was added and the solution was allowed to warm to room temperature over approximately 2 h and was stirred subsequently at room temperature for 16 h. The reaction mixture was diluted with C H 2 C I 2 (-100 mL), washed with ice-cold 0.5 M HC1 (2 x 25 mL), water (2 x 50 mL) and brine (3 x 50 mL), dried over anhydrous MgSC»4 and concentrated to provide the crude product as a pale yellow oil. Purification of the oil by flash chromatography (75% Et20 -pet . ether) provided pure keto-aldehyde 198 as a clear, colorless oil (0.5844 g, 89%) [N.B. Due to the air sensitivity of (198), this compound was stored at - 1 0 °C under argon]. ! H N M R ( C D C I 3 , 400 MHz): 6 9.48 (s, 1 H ; -CHO), 3.69-3.85 (m , .4H; - O C H 2 C H 2 O - ) , 2.46-2.55 (m, 2H; H(9A), HQ)), 2.29 (dd, J = 16.0, 10.0 Hz; H(9B)), 2.12 (s, 3H; H(7)), 1.90-2.05 (m, 3H; H(10), H(2A), H(3A)), 1.75-1.85 (m, 1H; H(3B)), 1.34-1.46 (m, 1H; H(2B)), 1.07 (s, 3H; C ( 5 ) -CH3) , 0.69 (d,7 = 6.5 Hz, 3H; C(10)-CH3). 13C N M R (CDC13, 50 MHz): 5 208.2 (C(8)), 207.5 (-CHO), 121.6 (C(4)), 65.5 ( - O C H 2 -C H 2 0 ) , 64.2 ( - O C H 2 C H 2 O - ) , 59.5, 48.9,48.6, 34.49, 31.5, 30.7, 25.4, 19.5, 10.3. IR (neat film): 2977, 2882, 2731 ( V C _ H , aldehyde), 1718 (vc=o), 1468, 1362, 1158, 1069 cm"1. EIMS mlz (rel intensity): 254 (0.7), 236 (0.4), 225 (0.3), 196 (1.1), 181 (1.0), 99 (100). Exact mass calcd for C14H22O4 254.1518, found 254.1511. 159 Table 5.13. Spectral Data from COSY Si Dectrum of Keto-aldehyde 198. 400 MHz ! H NMR Spectrum Signal Positions [S (ppm)] Assign-ment COSY Correlations Signal Positions [8 (ppm)] Assignment 2.46-2.55 H ( 1 , 9 A ) 2.29, 1.90-2.05, 1.34-1.46 H ( 9 B , 2 A , 2 B ) 2.29 H ( 9 B ) 2.46-2.55 (part of multiplet) 1.90-2.05 (part of multiplet) H ( 9 A ) , H(10) 1.90-2.05 H(10), H ( 2 A . 3 A ) 2.46-2.55, 2.29,1.75-1.85, • 1.34-1.46 H ( 1 , 9 A , 9 B , 2 B ) H(10 , 3 B ) C(10)-Me 1.75-1.85 H(3 B ) 1.90-2.05 (part of multiplet) 1.34-1.46 H ( 2 A , 3A) , H ( 2 B ) 1.34-1.46 H(2 B ) 2.46-2.55 (part of multiplet) 1.90-2.05 (part of multiplet) 1.75-1.85 H(l), H ( 2 A , 3A), H ( 3 B ) 0.69 C(10)-Me 1.90-2.05 (part of multiplet) H(10) Bicyclic Ketal-enone (200) To a solution of keto-aldehyde (198) (0.1184 g, 0.4655 mmol) in spectro grade methanol (5.0 mL) was added, in one portion, a 10% aqueous potassium hydroxide solution (1.3 mL, 130 mg, 2.3 mmol). The reaction mixture was stiiTed at room temperature under argon for 12 days after which it was neutralized by addition of 1 M HC1 (-2.7 mL). The mixture was extracted with diethyl ether (3 x 25 mL). The combined extracts were washed with brine (2 x 50 mL), dried over anhydrous MgS04, and evaporated to yield the intermediate aldol 199 as a viscous, colorless syrup that was used in the subsequent part without further purification. 160 Bicyclic Hydroxy-ketone (199) 1 H N M R ( C D C I 3 , 400 MHz): 8 4.19 (bs, 1 H ; exchanges with D 2 0 ; -OH), 3 . 9 7 ^ . 0 2 (m, 1 H ; H(6)), 3 .89-3.97 (m, 4 H ; - O C H 2 C H 2 O - ) . 3.36 (dd, / = 11 .0 , 4 . 0 Hz, 1 H ; H (9A ) ) , 2.83-2.92 (m, 1 H ; H(l)), 2.58-2.65 (m, 2 H ; H(7.)), 2 . 3 4 (dd, J = 1 1 . 0 , 5 .5 Hz, 1 H ; H ( 9 B ) ) , 2 . 1 0 - 2 . 2 2 (m, 1 H ; H (10) ) , 1.73-1 .90 (m, 3 H ) , 1.61-1.72 (m, 1 H ) , 0.96 (d, J = 8.5 Hz, 3 H ; C(10)-CH3_). !3C N M R (CDCI3,75 MHz): 8 2 1 1 . 9 (C(8)), 121 .2 (C(4)), 68.4 (C(6)), 64.9 ( - O C H ^ C H 2 0 - ) , 63.4 ( - O C H 2 C H 2 O - ) , 52.4, 50.0,46.5,42.0,32.8,31.2,22.3,15.8,14.9. IR (neat film): 3513 (broad, V 0 _ H ) , 2958, 2924, 2878, 1692 (vc=o), 1476, 1457, 1436, 1351, 1328, 1315 cm-1. EIMS mlz (rel intensity): 254 ( M + ; 52.8), 237 (12 .0 ) , 225 (4 .4 ) , 2 1 2 ( 1 1 . 1 ) , 192 (10.8), 183 (22 .4 ) , 9 9 (100). Exact mass calcd for C14H22O4:. 254.1518, found 254.1510. To an ice-cold solution of aldol 199, triethylamine (97 fiL, 0.071 g, 0.70 mmol), and DMAP (0.0568 g, 0.4649 mmol) in dry C H 2 C l 2 (5 mL) was added methanesulfonyl chloride (54 / /L , 0.080 g, 0.70 mmol). The cloudy, straw yellow solution was stirred at 0 °C for 2 h after which D B U (140 fiL, 0.142 g, 0.931 mmol), pre-purified by passage down a column of basic alumina, was added and the solution was allowed to warm to room temperature. The clear, pale yellow solution was stirred for 2 h and then poured into a 1:1 diethyl ether-water mixture (50 mL). The aqueous layer was extracted further with diethyl ether (2 x 25 mL). Combined extracts were washed with water (3 x 25 mL), saturated aqueous NaHC03 (3 x 25 mL), and brine (3 x 25 mL), dried over anhydrous MgS04, and concentrated to a pale yellow oil. Subsequent purification of the oil by flash column chromatography (70% Et 20-pet. ether) yielded pure ketal-enone (200) as a colorless oil (0.0768 g, 70% from the keto-aldehyde (198)). 161 Bicyclic Ketal-enone (200) l H N M R (CDCI3,400 MHz): 8 6.36 (d, / = 12.0 Hz, 1H; H(6)), 5.95 (dd, / = 12.0, 1.3 Hz, 1H; H(7)), 3.86-3.99 (m, 4 H ; - O C H 2 C H 2 O - ) , 2.62-2.72 (m, 2H; H(9)), 2.44-2.52 (m, 1H; H(l)), 2.23-2.30 (m, 1H; H(10)), 1.75-1.89 (m, 3H), 1.61-1.71 (m, 1H), 1.19 (s, 3 H ; C(5)-CH 3), 1.07 (d, J = 7.4 Hz, 3H; C(10)-CH 3). 13C N M R (CDCI3,100 MHz): 8 203.6 (C(8)), 149.4 (C(6)), 130.3 (C(7)), 119.1 (C(4)), 65.4 ( -OCH2CH2O-) , 64.0 ( - O C H 2 C H 2 O - ) , 53.4, 51.9,45.2, 31.6, 30.7,22.0,18.1,16.4. IR (neat film): 2959, 2878,1672 ( v c =o) , 1460,1286, 1241, 1165, 1061 cnr*. EIMS m/z (rel intensity): 236 (M+; 0.5), 221 (0.3), 208 (0.3), 193 (1.0), 99 (100). Exact mass calcd for C14H20O3: 236.1412, found 236.1415. Anal. Calcd for C i 4 H 2 o 0 3 : C, 71.16; H, 8.53. Found: C, 71.24; H, 8.57. Results of N O E Experiments: Irradiation of the signal at 8 1.19 ppm resulted in enhancements of signal intensities at 1.07, 1.75-1.89, and 6.36 ppm, while irradiation of the signal at 8 1.07 ppm resulted in enhancements of signal intensities at 1.19, 1.61-1.71, 1.75-1.89 (part of multiplet), 2.23-2.30, and 2.62-2.72 ppm. Keto-enone (202) 1 M HCl Z ^ ^ 1 0 \ acetone Xi--' v / O 202 Ketal-enone (200) (33.5 mg, 0.142 mmol) was dissolved in acetone (2.0 mL) and 1 M HCl (2.0 mL) was added. The colorless solution was stirred at room temperature for 3 h after which it was diluted with water (10 mL) and extracted with diethyl ether (3 x 25 mL). The combined extracts were washed with water (1 x 50 mL), saturated N a H C 0 3 solution (1 x 50 mL) and brine (3 x 50 mL), dried over anhydrous M g S 0 4 and concentrated under reduced pressure to afford a colorless oil. Subsequent purification of the oil by flash chromatography (70% Et20-pet. ether) yielded pure keto-enone (202) as a colorless film (24.4 mg, 90%). 162 ! H N M R (CDCI3,400 MHz): 5 6.87 (d, 7 =11.6 Hz, 1H; H(6)), 6.00 (dd, J = 11.6, 1.6 Hz, 1H; H(7)), 2.72 (d, J = 11.7 Hz, 1H; H(9A)), 2.66 (ddd, J =11.7, 7.1, 1.5 Hz, 1H; H(9B)), 2.12-2.58 (m, 4H), 1.90-1.98 (m, 2H), 1.22 (s, 3H; C(5)-CH 3), 1.12 (d, J = 7.0 Hz, 3H; C(10)-CH3). 13C N M R (CDCI3, 75 MHz): 3 216.8 (C=0), 201.9 (C=0), 148.8 (C(6)), 131.3 (C(7)), 55.2, 51.2, 47.5, 36.4, 30.9, 22.5, 18.3, 17.2. BR (neat film): 2965, 2930, 2876, 2860, 1740 (vC=o, saturated ketone), 1677 (vC=o, unsaturated ketone), 1625 (vc=c), 1464,1396,1381 cm" 1 EIMS mlz (rel intensity): 192 (M+; 100), 177 (7.1), 164 (52.0), 148 (41.3), 135 (48.3), 123 (84.0). Exact mass calcd for C i 2 H i 6 0 2 : 192.1150, found 192.1148. Anal. Calcd for C i 2 H i 6 0 2 : C, 74.97; H, 8.39. Found: C, 75.05; H, 8.42. Hydroxy-enone (158) To a solution of keto-enone (202) (15.7 mg, 81.6 jumol) in absolute ethanol (1.0 mL) at -10 °C was added solid sodium borohydride (0.9 mg, 22 jumol) in one portion. 1 0 3 The resulting clear, colorless solution was stirred at -10 °C for 10 min, and then neutralized by addition of 1 M HC1 (3 drops). The reaction mixture was diluted with diethyl ether (50 mL) and poured into water (25 mL). The aqueous phase was extracted further with diethyl ether (2 x 15 mL). The combined extracts were washed with saturated aqueous NaHC0 3 (1 x 25 mL) and brine (1 x 50 mL), dried over anhydrous MgS04, and concentrated to yield a colorless film. Flash column 163 chromatography (90% diethyl ether-pet. ether) yielded the desired hydroxy-enone (158) (13.4 mg; 85%) as a clear, colorless film; [a] ^  -20 (c 0.67, CHCI3). ! H N M R (CDCI3, 400 MHz): S 6.58 (d, / = 11.7 Hz, 1H; H(6)), 5.91 (dd, J = 11.7, 1.6 Hz, 1H; H(7)), 3.69 (dd, J = 8.0, 8.0 Hz, 1H; H(4)), 2.73 (dd, J = 11.0, 11.0 Hz, 1H; H(9A)), 2.59 (partially resolved ddd, J = 11.0, 7.7, 1.6 Hz, 1H; H(9B)), 2.20-2.30 (m, 1H), 1.95-2.11 (m, 2H), 1.84 (ddd, / = 19.0, 12.5, 5.3 Hz, 1H), 1.43-1.66 (m, 3H), 1.09 (s, 3H; C(5)-CH 3), 1.04 (d, / = 7.0 Hz, 3H; C(10)^CH3). N M R (CDCI3, 75 MHz): 8 203.8 (C(8)), 152.0 (C(6)), 129.5 (C(7)), 79.3 (C(4)), 51.4, 45.1,31.2, 29.7,28.8,22.7, 18.0, 11.7. IR (neat film): 3492 (broad, VO_H) , 2970,2875,1672 (vC=o), 1469,1391,1116,1070 cm" 1 EIMS mlz (rel intensity): 194 (M+; 40.4), 179 (5.8), 161 (7.5), 150 (100), 135 (37.2). Exact mass calcd for C12H18O2: 194.1307, found 194.1310. Hydroxy-ketone (128) 158 128 To a solution of hydroxy-enone (158) (10.2 mg, 51.9 jjmo\) in absolute ethanol (1.5 mL) was added 10% palladium on charcoal (2.5 mg). The mixture was stirred under an atmosphere of hydrogen (ambient pressure) for 4 h, then diluted with Et20 (50 mL) and filtered through a pad of Celite®. The Celite® pad was washed further with E t 2 0 (50 mL). The filtrate was concentrated to yield a clear, colorless film. Purification by flash column chromatography (90% 164 Et20-pet. ether) yielded pure hydroxy-ketone (128) as a clear, colorless film (9.4 mg; 93%); [a]25 -15 (c 0.47, CHCI3). ! H N M R (CDCI3, 400 MHz): 5 3.60 (dd, J = 8.5, 8.5 Hz, 1H; H(4)), 2.78 (dd, / = 11.2, 4.1 Hz, 1H; H(9A)), 2.40-2.52 (m, 3H; H(9B), H(7A), H(7B)), 2.03-2.14 (m, 2H; H(10), H(3A), 1.89 (ddd, / = 14.7, 4.5, 4.5 Hz, 1H; H(6A)), 1.65-1.79 (m, 2H; H(2A), H(l)), 1.36-1.61 (m, 4H; simplifies upon addition of D 2 0 ; H(2B), H(3B), H(6B), -OH) , 0.93 (d, J = 7.5 Hz, 3H; C(10)-CH3), 0.70 (s, 3H; C(5)-CH3). 13C N M R (CDCI3,75 MHz): S 213.6 (C(8)), 80.8 (C(4)), 51.7 (C(l)), 49.8 (C(9)), 46.6,41.2 (C(7)), 32.7, 31.4 (C(10)), 29.2 (C(3)), 23.4, 14.3 (C(10) -£H 3 ) , 11.3 (C(5)-CH3). IR (neat film): 3420 (broad, VO_H) , 2965,2870,1698 (vC=o), 1475,1391, 1112, 1075 cnv 1; EIMS m/z (rel intensity): 196 (18.3), 178 (64), 168 (73.6), 153 (42.1), 97 (100). Exact mass calcd for C12H20O2 196.1463, found 196.1472. Table 5.14. Results of NOE Experiments for Hydroxy-ketone 128. Proton Irradiated (ppm) Assignment NOE Correlations (ppm) Assignments* 3.60 H(4) 2.03-2.14 (part of multiplet) 1.89,1.65-1.79,1.36-1.61 H(3A), H(6A) 0.93 C(10)-Me 2.78,2.03-2.14,1.36-1.61, 0.70 H(9A), C(5)-Me 0.70 C(5)-Me 2.40-2.52,1.89,1.65-1.79, 1.36-1.61,0.93 H(6A), C(10)-Me *Only those protons that can be assigned unambiguously have been recorded. 165 Table 5.15. Spectral Data from COSY Spectrum of Hydroxy-ketone 128 400 MHz *H NMR Spectrum Signal Positions [S (ppm)] Assign-ment COSY Correlations Signal Positions [S (ppm)] Assignment 3.60 H(4) 2.03-2.14 (part of multiplet) 1.36-1.61 (part of multiplet) H(3A , 3B), - O H 2.78 H(9A) 2.40-2.52 (part of multiplet) 2.03-2.14 (part of multiplet), 0.93 H(9B), H(10), C(10)-Me 2.40-2.52 H(7A,7B) H(9B) 2.78, 2.03-2.14 (part of multiplet), 1.36-1.61 (part of multiplet) H(9A , 10) H(6A , 6B) 2.03-2.14 H(10,3A) 3.60, 2.78, 2.40-2.52 (part of multiplet), 1.65-1.79, 1.36-1.61 (part of multiplet), 0.93 H(4, 9A , 9B) H(2A , 2B, 3B) 1.89 H(6A) 2.40-2.52 (part of multiplet) 1.36-1.61 (part of multiplet) H(7 A ,7 B ) , H(6B) 1.65-1.79 H(1,2A) 2.03-2.14,1.36-1.61 (part of multiplet) H(10,2B), H(3A , 3B) 1.36-1.61 H(2 B ) 3B) H(6B), - O H 3.60, 2.40-2.52 (part of multiplet), 2.03-2.14 (part of multiplet), 1.89, 1.65-1.79 H(4,7 A , 7B), H(1,2A , 3A) H(6A) 0.93 C(10)-Me 2.78, 2.03-2.14 (part of multiplet) H(9A , 10) 166 Table 5.16. Spectral Data from HETCOR Spectrum of Hydroxy-ketone 128. 75 MHz 1 3 C NMR Spectrum Signal Positions [<5c (pPm)J Assign-ment HETCOR Correlations Signal Positions [8H (ppm)] Assign-ment 80.8 C(4) 3.60 H(4) 51.7 C(l) 1.65-1.79 (part of multiplet) H(l) 49.8 C(9) 2.78, 2.40-2.52 (part of multiplet) H(9) 41.2 C(7) 2.40-2.52 (part of multiplet) H(7) 32.7 C(6) 1.89,1.36-1.61 (part of multiplet) H(6) 31.4 C(10) 2.03-2.14 (part of multiplet) H(10) 29.2 C(3) 2.03-2.14 (part of multiplet), 1.36-1.61 (part of multiplet) H(3) 23.4 C(2) 1.65-1.79 (part of multiplet), 1.36-1.61 (part of multiplet) H(2) 14.3 C(10)-Me 0.93 C(10)-Me 11.3 C(5)-Me 0.70 C(5)-Me Keto-aldehyde (258) C 0 2 M e H O / N S ^ \ 1. (COCI)2 ,DMSO,CH 2 Cl2 , -78 0 C y ^ ^ y 2. E t 3 N , - 7 8 ° C - » r . t . 160 To a solution of oxalyl chloride (5.9 mL, 8.6 g, 68 mmol) in dry C H 2 C I 2 (50 mL) at -78 °C was added dropwise over 30 min a solution of dry DMSO (5.2 mL, 5.7 g, 73 mmol) in C H 2 C I 2 (50 m L ) . 1 0 0 The clear, colorless solution was stirred at -78 °C for 30 min after which a solution of the hydroxy-ester 160 (11.1537 g, 56.26 mmol) in C H 2 C I 2 (100 mL) was added dropwise by cannula over 30 min. The reaction mixture was stirred at -78 °C for a further hour. Triethylamine (23.5 mL, 17.1 g, 169 mmol) was added and the solution was allowed to warm to 167 room temperature over approximately 1.5 h and was stirred subsequently at room temperature for 10 h. The reaction mixture was diluted with water (~50 mL) and the organic layer withrawn. The aqueous layer was extracted further with CH2CI2 (2 x 50 mL). The combined extracts were washed with 1 M HCl (2 x 50 mL), water (2 x 50 mL), saturated aq. NaHCC>3 (1 x 50 mL), brine (3 x 50 mL), dried over anhydrous MgS04 and concentrated to provide the crude product as a pale yellow oil. Purification of the oil by flash chromatography (30% Et20-pet. ether) provided pure ester-aldehyde 258 as a clear, colorless oil (10.1841 g, 92%); [a]^ +47.2 (c 1.86, CHCI3). * H N M R (CDCI3,400 MHz): 8 9.21 (s, 1H; -CHO), 5.02 (dd, J = 2.0, 2.0 Hz, 1H; =CH A H B ) , 4.69 (dd, J = 2.0, 2.0 Hz, 1H; = C H A H B ) , 3.67 (s, 3H; -OMt). 2.61-2.71 (m, 1H; H(15A)), 2.42 (dddd, J = 17.0, 8.0, 4.5, 1.5 Hz, 1H), 2.28-2.38 (m, 1H; H(17)), 2.26 (dd, J = 7.4, 2.5 Hz, 2H; - C H 2 C 0 2 M e ) , 1.89-1.99 (m, 1H; H(16A), 1.36-1.49 (m, 1H; H(16B); 0.97 (s, 3H; C(13)-CH3). 1 3 C N M R (CDCI3, 75 MHz): 5 200.4 ( -£HO), 172.5 ( - £ 0 2 M e ) , 153.5 (H2C=C_), 110.1 (H2£=C) , 59.5 (C(13)), 51.5 (-COJMQ). 41.0 (C(17)), 31.2, 31.7, 29.9, 15.8 (C(13)-£ H 3 ) . IR (neat film): 3090 (v=c_H), 2960, 2895,2850, 2820, 2725 (V_CHO), 1740 (vC=o, ester), 1710 (vc=0, aldehyde), 1650 (v C = C ) , 1438, 1198, 898 cm-* EIMS m/z (rel intensity): 182 ( M + ; 10.5), 167 ((M - C H 3 ) + ; 24.5), 151 ((M - OMe) + ; 11.5), 123 (19.9), 107 (100). Exact mass calcd for C n H i 6 0 3 : 196.1099, found 196.1091. Anal. Calcd for C n H i 6 0 3 : C, 67.32; H, 8.22. Found: C, 67.21; H, 8.36. 168 Unsaturated Diester (259) ^ - C 0 2 M e 12 z : . 2 < ^ - C 0 2 M e (MeO)2P(0)CH2C02Me, NaH, T H F 258 259 To a suspension of sodium hydride (2.67 g, 60% dispersion in mineral oil; 1.5968 g, 66.54 mmol) in THF (100 mL) was added a solution of trimeUiyl phosphonoacetate (10.8 mL, 12.1 g, 66.5 mmol) in THF (100 mL) dropwise over 15 min. The resulting thick, white, pasty mixture was stirred at room temperature for 1.5 h. A solution of ester-aldehyde 258 (10.1063 g, 55.43 mmol) in THF (100 mL) was added dropwise over 30 min, after which the reaction mixture was stirred for a further 18 h. Water (100 mL) and Et20 (100 mL) were added, and the organic layer was withdrawn. The aqueous phase was extracted further with Et20 (2 x 100 mL). The combined organic phases were washed with water (3 x 100 mL) and brine (3 x 100 mL), dried over anhydrous MgSC»4, and evaporated to yield a pale yellow oil. Subsequent purification by flash column chromatography [30% Et20-pet. ether] yielded pure unsaturated diester 259 (12.4625 g, 96%) as a clear, colorless oil; [a]2£ +38.3 (c 1.00; CHC13). *H N M R (CDCI3,400 MHz): 8 6.88 (d, J = 16.0 Hz, 1H; Me02C-CH=CH-), 5.85 (d, J = 16.0 Hz, M e 0 2 C - C H = C H - ) , 4.93 (dd, / = 2.5, 2.5 Hz, 1H; = C H A H b ) , 4.70 (dd, / = 2.5, 2.5 Hz; 1H; = C H A H b ) , 3.75 (s, 3H; -C02Me), 3.65 (s, 3H; -CO>Me\ 2.50-2.58 (m, 1H), 2.40-2.48 (m, 1H), 2.28-2.39 (m, 2H), 2.11-2.20 (dd, J = 15.1, 9.5 Hz, 1H; - C H A H B C 0 2 M e ) , 1.97-2.05 (m, 1H; H(16A)), 1.43-1.53 (m, 1H; H(16B)), 1-02 (s, 3H; C(13)-CH 3). 13C N M R (CDCI3, 75 MHz): 8 172.7 (-C0 2Me), 166.8 (-C0 2 Me), 157.3 (H 2C=C), 155.0 (C(12)), 119.0 (C(ll)), 107.6 (H2£=C), 51.2 (-C0 2 Me), 50.5 (C(20), 45.6 (C(17)), 34.3, 30.4, 28.7, 18.5 (C(13)-CH3). 169 IR (neat film): 3090 ( V ^ - H ) , 2960, 2925, 2855, 1735 (vc=o, saturated ester), 1720 (vc=o, unsaturated ester), 1650 (vc=c), 1438, 1312,1095,1076, 890 cm-1 EIMS mlz (rel intensity): 254 ( M + ; 3.2), 223 ((M - OMe) + ; 51.3), 195 ((M - C 0 2 M e ) + ; 14.5), 180 (65.2), 107 (100). Exact mass calcd for C14H20O4: 252.1361, found 252.1367. Anal. Calcd for C14H20O4: C, 66.65; H, 7.99. Found: C, 66.76; H, 8.01. Diacid (261) To a solution of the unsaturated diester 259 (12.4020, 49.154 mmol) in dry methanol (300 mL) at 0 °C was added magnesium turnings (3.584 g, 147.5 mmol) in small portions over 20 min . 1 3 1 The solution was stirred at 0 °C for 2 h, allowed to warm to room temperature, and stirred for a further 12 h at room temperature. A solution of potassium hydroxide (6.89 g, 123 mmol) in water (250 mL) was added and the resulting thick, translucent mixture was stirred vigorously for 2.5 h. The reaction mixture was poured into an ice-cold 1 M HC1 (-300 mL) and neutralized by further addition of 6 M HC1 (-15 mL). The aqueous mixture was extracted with ethyl acetate (3 x 250 mL). The combined extracts were washed with water (2 x 250 mL) and brine (3 x 250 mL), dried over anhydrous MgS04, and concentrated to a viscous, colorless oil. Trituration of the oil in ice-cold pet. ether (-20 mL) followed by filtration of the resulting solid yielded pure diacid 261 as a white, crystalline solid (9.5937 g, 86%); [a]2£ +59.1 (c 0.89, CHCI3). 170 1H N M R ( C D C I 3 , 400 MHz): 8 11.20-12.50 (bs, 2H; - C O 2 H ) , 4.93 (dd,7 = 2.5, 2.0 Hz, 1H; = C H A H b ) , 4.72 (dd, J = 2.5, 2.0 Hz, 1H; =CHAHB), 2.43-2.55 (m, 2H), 2.24-2.38 (m, 3H), 2.13-2.20 (m, 1H), 2.00-2.10 (m, 2H), 1.85-1.95 (m, 2H), 1.30-1.42 (m, 1H), 0.89 (s, 3H; C(13)-CH3). 13C N M R (CDCI3, 75 MHz): 8 181.0 ( -C0 2 H), 180.2 ( -C0 2 H), 157.6 (H 2C=C), 105.2 (H2DO, 47.0, 41.3, 34.7, 32.0, 31.3, 29.4, 28.6, 23.8. IR (neat film): 3450-2300 (broad, V 0 - H ) , 2960, 2945,1710 (vc=o), 1655 (vc=c), 1410, 1302, 885 cm*1 EIMS m/z (rel intensity): 208 ( ( M - H 2 0 ) + ; 23.0), 190 (6.7), 180 (5.7), 16 (50.7), 153 (100). Exact mass calcd for C i 2 H i 6 0 3 ( ( M - H 2 0 ) + ) : 208.1099, found 208.1112. Anal. Calcd for C i 2 H i 8 0 4 : C, 63.70; H, 8.02. Found: C, 63.66; H, 7.89. Bicyclic Enone-ester (ent-255) 261 ent-255 To a solution of diacid 261 (9.3180 g, 41.18 mmol) was dissolved in dry C H 2 C 1 2 (600 mL) and trifluoroacetic anhydride (14.5 mL, 21.6 g, 103 mmol) was added in one portion. 1 3 2 The originally colorless reaction mixture, which darkened over time to a pale straw-yellow color, was stirred at room temperature for 2.5 h. The solvent was removed under reduced pressure to leave a dark-brown, viscous syrup. The syrup was dissolved in dry methanol (250 mL) and p-toluenesulfonic acid (0.7833 g, 4.118 mmol) was added. The colorless reaction mixture was stirred for 15 h, and the solvent was then removed under reduced pressure. The resulting orange-brown oil was partitioned between ethyl acetate (300 mL) and water (100 mL). 171 The organic phase was withdrawn, while the aqueous phase was extracted once more with ethyl acetate (100 mL). The combined organic layers were washed with saturated aq. NaHC03 (2 x 250 mL), brine (3 x 250 mL), dried over anhydrous MgS04, and concentrated under reduced pressure to yield a yellow-brown oil. Further purification of this oil by flash column chromatography [75% Et20-pet. ether or 60% EtOAc-pet. ether] yielded pure ester-enone ent-255 (8.0121 g, 89%) as a clear, colorless oil; [a]2£ -84.5 (c 1.00, CHCI3). *H N M R (CDCI3, 400 MHz): 8 5.80 (s, 1H; H(8)), 3.71 (s, 3H; -OMeJ, 2.68 (ddt, 18.0, 11.2, 2.1 Hz, 1H; -CH2C(0)-), 2.44-2.57 (m, 3H; -CH 2 C(0)- , - C H 2 C 0 2 M e , H(12A)), 2.39 (ddd, J = 18.0, 5.4, 2.1 Hz, 1H; H(12B)), 2.30 (dd, J = 15.0, 9.2 Hz, 1H; -CH^CC^Me), 2.05-2.14 (m, 2H; H(16A), H(17)), 1.97 (ddd, 7 = 15.0, 6.2, 2.1 Hz, 1H; H(15A)), 1.80 (ddd, / = 15.0, 14.5, 2.0 Hz, 1H; H(15B), 1.54-1.66 (m, 1H, H(16B)), 1.05 (s, 3H; C(13)-CH 3 ) . 1 3 C N M R (CDCI3, 50 MHz): 8 198.7 (C(9)), 177.5 ( - £ 0 2 M e ) , 173.0 (C(14)), 122.0 (C(8)), 51.6 (-C0 2Me), 46.7 (C(17)), 44.1, 34.6, 34.0, 33.1, 27.4, 27.4, 16.4 (C(13)-CH3). IR (neat film): 2950, 2928, 2882, 1740 (vc=o, ester), 1662 (vC=o, enone), 1622 (vC=c), 1438, 1198,1170,999 cm-1 EIMS m/z (rel intensity): 222 ((M + ; 33.6), 207 ((M - C H 3 ) + ; 15.4), 194 (22.4), 191 (21.8), 180 (43.2), 121 (100). Exact mass calcd for C13H18O3 : 222.1256, found 222.1260. Anal. Calcd for C13H18O3 C, 70.24; H, 8.16. Found: C, 69.98; H, 8.00. 172 Ketal-ester (262) C 0 2 M e 20 C 0 2 M e O ent-255 ( C H 2 O H ) 2 , P P T S , C 6 H 6 reflux 262 To a solution of (+)-enone-ester ent-255 (7.8219 g, 35.18 mmol) in benzene (200 mL) was added pyridinium p-toluenesulfonate (1.7682 g, 7.04 mmol) and the mixture was refluxed for 18 h. The reaction mixture was partitioned between brine (100 mL) and ether (100 mL). The organic phase was separated, while the aqueous phase was extracted with ether (2 x 100 mL). The combined extracts were washed with water (2 x 250 mL), saturated aqueous NaHCC»3 (2 x 250 mL), and brine (3 x 250 mL), dried over anhydrous MgSC»4, and concentrated to a pale yellow oil. Subsequent purification by flash column chromatography (20% EtOAc-pet. ether) yielded ketal-ester 262 (7.6827 g, 82%) as a clear, colorless oil; [a]2£ -16.3 (c 0.99, CHCI3). ! H N M R ( C D C I 3 , 4 0 0 MHz): 8 5.33 (m, 1H), 3.93^1.00 (m, 4H; - O C H 2 C H 2 O - ) , 3.67 (s, 3H; -OMe), 2.32-2.52 (m, 6H), 1.99-2.07 (m, 1H), 1.79-1.88 (m, 1H), 1.65-1.74 (m, 2H), 1.51-1.59 (m, 1H), 0.92 (s, 3H; C(13)-CH3). IR (neat film): 2960, 2900, 2860,1742 (vC =o, ester), 1438,1360,1096, 1022 cm"1 EIMS mlz (rel intensity): 266 ( M + ; 2.1), 235 ((M - OMe) + ; 1.2), 99 (100). Exact mass calcd for C15H22O4 266.1518, found 266.1522. Anal. Calcd for C15H22O4: C, 67.65; H, 8.33. Found: C, 67.47; H, 8.30. 173 Ketal-diester (263) 23 ^ - C 0 2 M e ^ C 0 2 M e 21 \ ^ - C 0 2 M e ;20 2. BrCH 2 C02Me, /i-Bu4N + I , -78 °C-> r.t. l . L D A , T H F , - 7 8 ° C o O o 262 263 To a solution of diisopropylamine (2.68 mL, 1.93 g, 19.1 mmol) in THF (25 mL) at 0 °C was added n-butyllithium (12.3 mL, 1.55 M in hexane, 19.1 mmol) dropwise over 5 min. The solution was stirred at 0 °C for 30 min, then cooled to -78 °C. A solution of ketal-ester 262 (3.9163 g, 14.704 mmol) in THF (40 mL) at -78 °C was added by cannula and the reaction mixture was stirred for 30 min. Methyl bromoacetate (2.78 mL, 4.50 g, 29.4 mmol) and solid tetrabutylammonium iodide (2.7157 g, 7.352 mmol) 1 3 3 were added successively to the reaction mixture. The solution was allowed to warm to room temperature over ~2 h and was stirred for a further 16 h. Water (-100 mL) was added and the organic phase was separated. The aqueous phase was extracted further with ether (3 x 50 mL). The combined extracts were washed successively with saturated aqueous Na2S2C«3 solution (2 x 50 mL), water (1 x 50 mL), and brine (3 x 100 mL), dried over anhydrous MgS04, and concentrated under reduced pressure to yield a pale yellow oil. Subjection of the crude product to flash column chromatography (20% EtOAc-pet. ether) yielded recovered starting material (0.3129 g) and upon further elution, the desired ketal-diester 263 (4.2495 g, 93% based on recovered starting material) as a clear, colorless oil. 1H N M R (CDCI3,400 MHz): <5 5.27 (bs, 1H; H(15)), 3.84-4.00 (m, 4H; -OCH3CH2O-), 3.68 (s, 3H, -CO2MS), 3.64 (s, 3H, -CC"?Me), 2.93 (ddd, J = 11.0, 11.0, 4.1 Hz, 1H; H(20)), 2.66 (dd, J = 16.4, 11.0 Hz, 1H; H(22)); 2.48 (dd, / = 16.4, 4.2 Hz, 1H; H(22)); 2.27-2.41 (m, 3H; H(16), H(8A), H(8B)), 2.09-2.18 (m, 1H; H(17)), 1.94-2.05 (m, 1H; 174 H(16)), 1.76 (ddd, J = 14.9, 14.9, 4.4 Hz, 1H; H(11A)), 1.39-1.65 (m, 3H); H(12A), H(12B), H(11B)), 1.03 (s, 3H; H(18)). N M R (CDCI 3 , 75 MHz): 8 175.4 (^C0 2Me), 172.4 (-C0 2 Me), 148.1 (C(14)), 120.5 (C(15)), 109.0 (C(9)), 64.5 ( - O C H 2 C H 2 0 - ) , 64.4 ( - O C H 2 £ H 2 0 - ) , 53.9 (C(20)), 51.8 (-OMs), 51.7 (-OMe). 45.6, 42.2 (C(17)), 36.6, 36.2, 35.8, 35.0, 31.0, 15.5. IR (neat film): 2951, 2890, 1741 (vc=o), 1665 (vc=c), 1437, 1360, 1265, 1207, 1165, 1096 cm - 1 EIMS mlz (rel intensity): 338 (M+; 1.9), 323 (0.1), 307 (2.5), 276 (0.6), 265 (0.2), 249 (0.5), 99 (100). Exact mass calcd for CigH 2 6 06: 338.1729, found 338.1729. Anal. Calcd for C i 8 H 2 6 0 6 : C, 63.89; H, 7.74. Found: C, 63.98; H, 7.77. Ketal-diol (264) To a solution of ketal-diester 263 (2.4967 g, 7.378 mmol) in dry T H F (35 mL) at 0 °C was added DIBAL (32 mL, 1 M in THF, 32 mmol) dropwise over 11 min. The colorless solution was stirred at 0 °C for 90 °C. Water (20 mL) was added dropwise and the mixture was stirred at room temperature for 2 h. A further portion of water (100 mL) was added and the organic layer was separated. The aqueous layer was extracted further with ether (5 x 50 mL). The combined organic extracts were washed with brine (3 x 100 mL), dried over anhydrous MgS04 and concentrated to provide a colorless, viscous syrup. Subsequent purification by flash 175 column chromatography (45% acetone-pet. ether) yielded pure ketal-diol 264 as a clear, viscous syrup (1.7764 g, 85%). 1H N M R (CDCI 3 , 400 MHz): S 5.21 (bs, 1H; H(15)), 3.87-3.98 (m, 4H; - O C H 2 C H 2 0 - ) , 3.74-3.83 (m, 2H; H(22A), H(21A)), 3.64-3.71 (m, 1H; H(22B)), 3.55 (dd, J = 11.2, 6.1 Hz, 1H; H(21B)), 2.68 (bs, 2H; - O H , -OH), 2.25-2.42 (m, 3H), 1.78-2.06 (m, 6H), 1.53-1.70 (m, 3H), 0.98 (s, 3H; C(13)-CH3). " C N M R ( C D C I 3 , 75 MHz): 5 147.6 (C(14)), 121.7 (C(15)), 109.1 (C(9)), 64.6, 64.5, 64.4, 60.6 (C(21), C(23), - O C H 2 C H 2 O - ) , 51.5 (C(20) or C(17)), 45.9, 40.0 (C(17) or C(20)), 37.9, 36.4, 35.7, 34.4, 31.2,15.9. IR (neat film): 3340 (VO_H), 2930,1620 (v c =c), 1438,1378,1110,1072 cm"1 DCI-MS (NH3) mlz (rel intensity): 283 ((M+H)+; 96.0), 282 (M+; 5.2), 265 ((M-OH) + ; 13.2), 221 (23.5), 99(100). Exact mass calcd for C16H26O4: 282.1831, found 282.1840. Dimethoxy-ketal (265) To a suspension of sodium hydride (94.6 mg, 60% dispersion in mineral oil, 3.94 mmol) in THF (10 mL) was added a solution of ketal-diol 264 (445.2 mg, 1.577 mmol) in THF (10 mL) and the resulting mixture was stirred for 1 h at room temperature. Methyl iodide (0.25 mL, 0.56 g, 3.9 mmol) was added and the reaction was allowed to proceed for a further 8 h at room temperature. Water (-50 mL) was added dropwise, cautiously at first, and the organic layer was 176 separated. The aqueous layer was extracted further with ether (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL) dried over anhydrous MgSC>4 and concentrated under reduced pressure to give a yellow-orange oil. Subsequent purification by flash column chromatography (30% EtOAc-pet. ether) yielded pure dimethoxy-ketal 265 (439.4 mg, 90%) as a clear, colorless oil. 1 H N M R ( C D C 1 3 , 400 MHz): 8 5.30 (bs, 1H; H(15)), 3.87-3.98 (m, 4H; - O C H 2 C H 2 O - ) , 3.38-3.44 (m, 3H; H(21A), H(23A), H(23B)), 3.24-3.32 (m, 1H; H(21B)), 3.31 (s, 3H; -OMe), 3.27 (s, 3H; -OMt). 2.27-2.42 (m, 3H; H(16A), H(8A), H(8B)), 1.89-2.05 (m, 2H; H(16B), H(11A)), 1.70-1.89 (m, 4H; H(22A), H(20), H(11B), H(12A)), 1.49-1.67 (m, 3H; H(22B), H(17), H(12B), 0.96 (s, 3H; C(13)-CH3). 13C N M R (CDCI3, 75 MHz): 8 173.7 (-C0 2Me), 146.9 (C(14)), 121.5 (C(15)), 109.2 (C(9)), {64.4, 64.3 ( -OCH2CH2O- ) } , 51.3,47.6, 45.6, 36.7, 36.3, 36.2, 34.8, 31.0, 16.3 (C(13>-CH 3 ) . IR (neat film): 2947, 2883, 2805, 1455, 1355, 1106, 955, 798 cm-1 EIMS m/z (rel intensity): 310 (M + ; 9.1), 278 ((M - M e O H ) + ; 1.1), 265 (12.0), 195 (5.0), 147 (10.9), 99(100). Exact mass calcd for C i 8 H 3 o 0 4 : 310.2144, found 310.2143; Anal. Calcd for C18H30O4: C, 69.64; H, 9.74. Found: C, 69.71; H, 9.75. 177 Dimethoxy-enone (267) 23 OMe OMe 22 OMe OMe o. 1 M HCl , acetone O o 265 267 A solution of dimethoxy-ketal (265; 0.4394 g, 1.415 mmol) and 1 M HCl (8 mL) in acetone (8 mL) was stirred at room temperature for 2 h. The reaction mixture was poured into brine (100 mL) and the aqueous solution was extracted with ether (3 x 50 mL). Subsequently, the combined organic phases were neutralized with saturated NaHC03 (3 x 50 mL) washed with water (1 x 100 mL) and brine (3 x 100 mL) dried over anhydrous MgS04 and evaporated under reduced pressure to yield a cloudy, colorless oil. Subsequent purification by flash column chromatography (60% EtOAc-pet. ether) yielded pure dimethoxy-enone 267 (0.2970 g, 92%) as a clear, pale yellow oil. * H N M R (CDC1 3, 400 MHz): 8 5.71 (bs, 1H; H(9)), 3.42 (bd, / = 5.7 Hz, 1H; H(23A)), 3.40 (bd, J = 5.7 Hz, 1H; H(23B)), 3.30-3.36 (m, 2H; H(21A), H(21b)), 3.31 (s, 3H; -OMe), 3.27 (s, 3H; -OMe), 2.62 (ddt, J = 19.8, 10.8, 2.2 Hz, 1H; H(15A)), 2.35-2.55 (m, 2H; H(11A), H(15B)), 2.30 (dddd, J = 17.8, 5.0, 1.3, 0.7 Hz, 1H; H(11B)), 2.08 (ddd, / = 13.2, 5.3, 2.2 Hz, 1H; H(12A)), 1.95 (dddd, J = 12.5, 12.5, 6.6, 2.2 Hz, 1H; H(16A)), 1.86 (ddd, J = 13.5, 13.5, 5.0 Hz, 1H; (H(12B)), 1.71-1.81 (m, 3H; H(17), H(20), H(22A)), 1.50-1.66 (m, 2H; H(16B), H(22B)), 1.08 (s, 3H; C(13)-CH3). IR (neat film): 2980,2948,2902,2835,1660 (vC=o), 1456,1202,1106 cnr 1 EIMS mlz (rel intensity): 266 (M+; 16.6), 251 ((M - C H 3 ) + ; 46.5), 234 ((M - MeOH) + ; 202 ((M - 2MeOH) + ; 15.1), 121 (94.0). Exact mass calcd for C16H26O3: 266.1882, found 266.1880. Anal. Calcd for C16H26O3: C, 72.14; H, 9.84 Found: C, 72.20; H, 9.86. 178 Table 5.17. Spectral Data from COSY Spectrum of Dimethoxy-enone 267. 400 MHz ! H NMR Spectrum Signal Positions [8 (ppm)] Assign-ment COSY Correlations Signal Positions [8 (ppm)] Assignment 5.71 H(9) 2.61 H(15) 3.42 H(23A) 3.40,1.71-1.81 (part of multiplet) 1.50-1.66 (part of multiplet) H(22A, 22B) H(23B) 3.40 H(23B) 3.42,1.71-1.81 (part of multiplet) H(23A, 22A) 3.30-3.36 H(21A) H(21B) 3.30-3.36*, 1.71-1.81 (part of multiplet) H(21A,21B), H(20, 22A) 2.62 H(15A) 5.71, 2.35-2.55 (part of multiplet) 1.95, 1.50-1.66 (part of multiplet) H(15B,9) H(16A, 16B) 2.35-2.55 H(11A), H(15B) 2.62, 2.30, 2.35-2.55 (part of multiplet), 2.08, 1.95, 1.86, 1.50-1.66 (part of multiplet) H(11 a ,11B), H(12A, 12B) H(16A, 16B) H(15A) 2.30 H(11B) 2.35-2.55 (part of multiplet), 2.08, 1.86 H(ll) , H(12A,12B) 2.08 H(12A) 2.35-2.55 (part of multiplet), 2.30, 1.86 H ( 1 1 A , H B ) H(12B) 1.95 H(16A) 2.62, 2.35-2.55 (part of multiplet), 1.71-1.81 (part of multiplet), 1.50-1.66 (part of multiplet) H(15A, 15B), H(16B), H(17) 1.86 H(12B) 2.35-2.55 (part of multiplet), 2.30, 2.08 H(11A, H B ) , H(12A) 1.71-1.81 H(17), H(20), H(22A) 3.42, 3.40, 3.30-3.36,1.95, 1.50-1.66 H(21A,21B), H(23A, 23B), H(16A, 16B), H(22B), 1.50-1.66 H(16B) H(22B) 3.42,2.62,2.35-2.55 (part of multiplet), 1.95,1.71-1.81 (part of multiplet) H(23A, 22A), H(15A, 15B), H(16A) 179 (±)-l-Chloro-3-pentanol (274) / \ ^ - ^ ^ C l N a B H 4 , MeOH, 0 °C O 272 To a solution of distilled l-chloro-3-pentanone (272; 5.9420 g, 49.28 mmol) in methanol (50 mL) at 0 °C was added solid sodium borohydride (1.3982 g, 36.96 mmol) in several portions over 10 min. The clear, colorless solution was stirred at 0 °C for 30 min. 1 M HCl (~10 mL) and brine (50 mL) were added and the solution was extracted with Et20 (3 x 50 mL). The combined extracts were washed with water (1 x 50 mL), saturated aq. NaHCC»3 (2 x 50 mL) and brine (3 x 50 mL), dried over anhydrous MgS04, and concentrated under reduced pressure to yield (±)-l-chloro-3-pentanol (274) as a colorless liquid (5.5241 g, 95%) that could be used in the subsequent reaction without further purification. 1H N M R (CDC1 3, 200 MHz): 8 3.65-3.80 (m, 3H; H(l), H(3)), 2.06 (bs, 1H; exchanges with D2O; -OH), 1.82-1.96 (m, 2H; H(2)), 1.53 (dt,7 = 9.5, 8.0 Hz, 2H; H(4)), 0.95 (t, / = 8.0 Hz, 3H; H(5)). IR (neat fdm): 3332 (broad, VQ-H), 2966, 2931,2879,1459 cm"1. (±)-l-Chloro-3-(*-butyldiphenyIsiIyloxy)pentane (275b) ci TBDPS-C1, imidazole To a solution of (±)-l-chloro-3-pentanol (274; 5.3277 g, 43.46 mmol) and imidazole (14.8275 g, 217.80 mmol) in spectro D M F (40 mL) was added f-butyldiphenylsilyl chloride (13.3 mL, 14.3 g, 52.2 mmol). 9 3 The colorless solution was stirred for 3 h after it was partitioned between water (50 mL) and Et20 (50 mL). The organic phase was removed while OTBDPS 275b 180 the aqueous phase was extracted further with Et20 (3 x 50 mL). The combined extracts were then washed with water (100 mL) and brine (3 x 100 mL), and dried over anhydrous MgSC»4. Subsequent concentration of the extracts under reduced pressure afforded (±)-l-chloro-3-(f-butyldiphenylsilyloxy)pentane (275b) as a viscous, colorless oil (15.3065 g, 98%) that could be used in the subsequent reaction without further purification. 1H N M R (CDCI3, 200 MHz): 8 7.60-7.72 (m, 4H; -C6H5), 7.25-7.40 (m, 6H; -C6H5), 3.82 (quint, J = 9.0 Hz, 1H; H(3)), 3.53 (t, J = 11.5 Hz, 2H; H(l)), 1.87-1.95 (m, 2H; H(2)), 1.45 (dt, J = 9.0, 8.0 Hz, 2H; H(4)), 1.04 (s, 9H; Bu<), 0.73 (t, / = 8.0 Hz, 3H; H(5)). IR (neat film): 3070 (V = C -H ) , 2955, 2940, 2857, 1592 (vc=c), 1427, 1109 cnr 1 . (±)-l-Iodo-3-(f-butyldiphenyIsilyloxy)pentane (270b) sS^+^s^^Cl Nal, acetone x ^ ^ / V ^ t OTBDPS reflUX OTBDPS 275b 270b A solution of l-chloro-3-(r-butyldiphenylsilyloxy)pentane (275b; 11.2798 g, 31.25 mmol) and anhydrous sodium iodide (9.3672 g, 62.49 mmol) in spectro grade acetone (200 mL) 134,136 Was refluxed for 24 h and then allowed to cool to room temperature. The reaction mixture was diluted with Et20 (100 mL), and poured into brine (100 mL). The organic layer was withdrawn while the aqueous layer was extracted with a further portion of Et20 (100 mL). The combined organic solutions were washed with saturated aq. NaHSC»3 (1 x 100 mL) and brine (2 x 100 mL). The solution was concentrated under reduced pressure to yield crude (±)-l-iodo-3-(f-butyldiphenylsilyloxy)pentane (270b) as a colorless oil. Further purification of the product 270b by flash column chromatography (5% Et20-pet. ether) yielded pure (±)-l-iodo-3-(f-butyldiphenylsilyloxy)pentane (270b) as a colorless syrup (10.8213 g, 77%). 181 1H N M R (CDCI3, 200 MHz): 8 7.60-7.70 (m, 4H; -CgHs), 7.25-7.40 (m, 6H; -C6H5), 3.63 (quint, / = 7.0 Hz, 1H; H(3)), 3.09 (t, / = 8.5 Hz, 2H; H(l)), 1.80-2.00 (m, 2H; H(2)), 1.38 (dt, J = 9.0, 8.0 Hz, 2H; H(4)), 0.99 (s, 9H; Bu'), 0.69 (t, J = 8.0 Hz, 3H; H(5)). IR (neat film): 3070 ( V = C _ H ) , 2956, 2940, 2857, 1592 (vc=c), 1466, 1100 cm"1. DCI-MS (NH 3) m/z (rel intensity): 453 ((M + H) + ; 58.0), 412 (37.2), 395 ((M - Bu') + ; 54.6), 196 (100). Exact mass calcd for C 2 iH 3 oIOSi [(M + H) +] 453.1070 , found 453.1111. Dimethoxy-enone (277) A suspension of sodium hydride (28.3 mg, 60% dispersion in mineral oil, 0.589 mmol) in dry, distilled DMSO (8 m L ) 1 3 8 was stirred at room temperature for 10 min and at 80 °C for 2 h. The mixture was cooled to room temperature, after which a solution of the bicyclic dimethoxy-enone 267 (130.8 mg, 0.491 mmol) in dry, distilled DMSO (2.5 mL) was added dropwise by syringe over 5 min. After a further 2 h, a solution of l-iodo-3-(r-butyldiphenylsilyloxy)pentane (270b; 288.8 mg, 0.638 mmol) in dry DMSO (2.0 mL) was added dropwise by syringe over 5 min. The reaction mixture was stirred for 18 h after which it was poured into a separatory funnel containing brine (25 mL) and ether (50 mL). The organic layer was withdrawn wile the aqueous layer was extracted further with ether (2 x 50 mL). The combined extracts were washed with water (50 mL) and brine (3 x 50 mL), dried over anhydrous MgS04, and concentrated to an 182 orange-yellow oil. Purification by flash column chromatography (30% EtOAc-pet. ether) yielded, in order of elution, the dienol ether 278 (80.6 mg) as a pale yellow oil, and then the desired bicyclic enone 277 (188.9 mg, 65%) as a pale yellow oil. Bicyclic Dimethoxy-enone (277) 1H N M R (CDC1 3 , 400 MHz): 5 7.60-7.72 (m, 4H; -C&H5), 7.30-7.42 (m, 6H; -C6H5), 3.69 (bquint, J = 5.5 Hz, 1H; H(5)), 3.38-3.45 (m, 2H; -CH^OMe), 3.30-3.35 (m, 2H; -CH 2 OMe) , 3.33 (s, 3H; -OMe). {3.28, 3.27 (s, 3H; -OMs)}, 2.41-2.53 (m, 1H), 2.16-2.38 (m, 3H), 1.96-2.10 (m, 3H), 1.84-1.94 (m, 1H), 1.64-1.82 (m, 5H), 1.38-1.60 (m, 4H), 1.23-1.36 (m, 1H), 1.04 (s, 9H; f-BuJ, 0.99 (s, 3H; C(18)), 0.77 (t, J = 7.4 Hz, 3H; C(10)-CH3). IR (neat film): 3070 (V^H) , 3055 (V=C_HX 2965, 2925, 2860, 1654 (vc=o), 1605.(vc=c), 1460,1428,1372,1191,1095 cm- 1 DCI-MS (NH 3) mlz (rel intensity): 590 ( M + , 0.2), 561 ((M - Et) +; 1.3), 547 (10.1), 533 ((M -BuO + ; 79.3). Exact mass calcd for C3 7H5404Si 590.3791, found 590.3805. Anal. Calcd for C37H5404Si: C, 75.19; H, 9.23 Found: C, 75.30; H, 9.10 183 /^Unsaturated Enone (279) 277 279 OTBDPS 281 A suspension of sodium hydride (28.0 mg, 60% dispersion in mineral oil, 0.583 mmol) in dry, distilled DMSO (8 m L ) 1 3 8 was stirred at room temperature for 10 min and at 80 °C for 2 h. The mixture was cooled to room temperature, after which a solution of the bicyclic enone 277 (265.0 mg, 0.4484 mmol) in dry, distilled DMSO (2 mL) was added dropwise by syringe over 5 min. After a further 2 h, a solution of methyl iodide (33.5 fjL, 76.4 mg, 0.538 mmol) in dry DMSO (0.5 mL) was added dropwise by syringe over 1 min. The reaction mixture was stirred for 6 h after which it was poured into a separatory funnel containing brine (25 mL) and ether (50 mL). The organic layer was withdrawn wile the aqueous layer was extracted further with ether (2 x 50 mL). The combined extracts were washed with water (50 mL) and brine (3 x 50 mL), dried over anhydrous MgS04, and concentrated to an orange-yellow oil. Purification by flash column chromatography (30% EtOAc-pet. ether) yielded, in order of elution, the dienol ether 281 (80.6 mg) as a pale yellow oil, and then the desired bicyclic enone 279 (217.6 mg, 80%) as a pale yellow oil. fi.y-Unsaturated Enone (279) 1H N M R ( C D C I 3 , 4 0 0 MHz): 8 7.49-7.69 (m, 4H; - C 6 H 5 ) , 7.30-7.42 (m, 6H; - C 6 H 5 ) , {5.31 (dd, J = 3.5, 1.4 Hz); 5.26 (dd, J = 3.5, 1.2 Hz), 1H; H(15)}, 3.55-3.65 (m, 1H), 3.39-3.46 (m, 2H), {3.34, 3.35 (s, 3H; -OMe)}, 3.29-3.38 (m, 2H), 3.28 (s, 3H; -OMe), 2.44-2.58 (m, 1H), 2.20-2.33 (m, 2H), 1.69-2.08 (m, 6H), 1.21-1.66 (m, 7H), 1.01 (s, 9H; t-184 Bu), {0.99, 1.06 (s, 3H)}, {0.90, 0.92 (s, 3H)}, {0.73 (t, J = 7.4 Hz); 0.77 (t, / = 7.5 Hz), 3H;C(10)-CH 3}. IR (neat film): 3071 (V = C _H) , 3052 (V=C_H), 2960, 2916, 2832, 1708 (vc=o)> 1460, 1427, 1378,1108 cm-1 EIMS mlz (rel intensity): 604 (M+; 0.6), 575 ((M - Et)+; 0.6), 561 (23.2), 547 ((M - Bu<)+; 44.7), 515 (4.3), 485 (5.2). Exact mass calcd for C38H5604Si: 604.3948, found 604.3908. Keto-alcohol (269) A solution of the silyloxy-ketone 279 (206.7 mg, 0.3417 mmol) and tetrabutylammonium fluoride (680 yL, 1 M in THF, 0.680 mmol) in THF (4.0 mL) was refluxed for 2 h before being diluted with Et20 (25 mL) and then poured into brine (20 mL). After the organic phase was removed the aqueous mixture was extracted with ether (5 x 20 mL). The combined extracts were washed with water (1 x 50 mL) and brine (3 x 50 mL), dried over anhydrous MgSC»4, and concentrated to a pale brown-yellow oil. Further purification by flash column chromatography (60% EtOAc-pet. ether) yielded pure keto-alcohol 269 as a clear, colorless, viscous film (113.0 mg, 90%). ! H N M R (CDC13,400 MHz): 8 {5.49 (partially resolved dd, / = 3.2,1.1 Hz); 5.44 (dd, J =3.6, 1.3 Hz), 1H; H(15)}, 2.58 (ddd, / = 17.6, 12.0, 5.8 Hz, 1H; H(ll)), 3.48 (bs, 1H; -OH), 185 3.29-3.45 (m, 5H; - C H 2 O M e , -CFJ20Me, H(5)), {3.30, 3.32 (s, 3H, -OMe)). {3.26, 3.27 (s, 3H, -OMe)}, 1.20-2.42 (m, 15H), {0.89 (t, J = 1A Hz); 1.02 (t, J = 7.2 Hz), 3H; H(19)}, {1.07, 1.16(s,3H,H(8'))}, {0.93,1.04 (s, 3H; H(18))}. IR (neat film): 3456 (broad; V 0 - H ) , 2955, 2945, 2870, 1709 (vc=o), 1457, 1375, 1244, 1109 cm - 1 EIMS m/z (rel intensity): 366 ( M + ; 11.5), 351 ((M - C H 3 ) + ; 7.2), 346 ((M - H 2 0 ) + ; 6.5), 335 (5.5), 316(1.5). Exact mass calcd for C 2 2 H 3 8 0 4 : 366.2770, found 366.2772. Diketone (268) 23 To a solution of keto-alcohol 269 (60.7 mg, 0.166 mmol) in acetone (5.0 mL) at 0 °C was added, dropwise over 1 min, a solution of chromium(VI) oxide (16.6 mg, 0.166 mol) and concentrated sulfuric acid (~0.3 mL) in water (1.0 mL). Saturated aqueous sodium bisulfite solution (~1 mL) was added and the reaction mixture was partitioned between brine (50 mL) and ether (50 mL). The organic layer was separated while the aqueous layer was extracted once more with ether (25 mL). The combined extracts were washed with water (2 x 50 mL), saturated aqueous sodium bicarbonate (3 x 50 mL) and brine (3 x 50 mL), dried over anhydrous MgS04, and concentrated to a pale yellow oil. Subsequent purification by flash column chromatography (20% EtOAc-pet. ether) yielded pure diketone 268 (52.7 mg, 87%) as a clear, colorless film. 186 ! H N M R (CDCI3, 400 MHz): 5 5.46 (dd, J = 3.4, 1.4 Hz, 1H, H(15)), 3.40-3.48 (m, 2H; H(21A), H(23A)), 3.31-3.38 (m, 2H; H(21B), H(23B)), 3.31 (s, 3H; -OMe). 3.27 (s, 3H; -OMe), 2.58 (ddd, J = 16.8, 11.2, 5.5 Hz, 1H; H(11A)), 2.16-2.42 (m, 5H; H(11B), H(10A,B), H(16A,B)X 1.90-2.05 (m, 4H), 1.69-1.89 (m, 5H), 1.51-1.62 (m, 1H; H(23)), 1.16 (m, 3H; H(8')), 1.01 (s, 3H, H(18)), 0.99 (t, J = 7.4 Hz, 3H; H(19)). IR (neat film): 2971, 2927, 2875,1713 (vc=o), 1460, 1376, 1114 cm"1 EIMS mlz (rel intensity): 364 ( M + ; 4.7), 349 ((M - C H 3 ) + ; 31.2), 332 (29.8), 314 (21.1), 301 (9.3). Exact mass calcd for C22H36O4: 364.2643, found 364.2622. Tricyclic Dienone (257) To a solution of diketone 268 (23.2 mg, 0.0636 mmol) in dry, distilled benzene (15 mL) was added p-toluenesulfonic acid (2.4 mg, 0.0127 mmol). The mixture was refluxed in a Dean-Stark apparatus for 2 h, allowed to cool to room temperature, diluted with ether (~25 mL), and washed successively with saturated aqueous sodium bicarbonate (2 x 25 mL), water (1 x 25 mL), and brine (3 x 25 mL). The organic phase was dried over anhydrous M g S 0 4 and then concentrated under reduced pressure to afford a orange-yellow film. Purification by flash column chromatography (20% EtOAc-pet. ether) yielded pure tricyclic enone 257 (18.6 mg, 84%) as a clear, colorless film; [a] ^  -12.5 (c 0.93, CHCI3). 187 1H N M R ( C D C I 3 , 4 0 0 MHz): 8 5.41-5.48 (m, 1H; H(15)), 3.44 (d, J = 6.2 Hz, 1H; H(23A)), 3.42 (d, J = 6.2 Hz, 1H; H(23B)), 3.38 (dd, J = 9.4, 3.4 Hz, 1H; H(21A)), 3.30-3.35 (m, 1H; H(21B)), 3.32 (s, 3H; -OMs), 3.29 (s, 3H; -OMe). 2.50-2.65 (m, 2H; H(17), H(6A)), 2.39 (ddd, J = 17.6, 4.7, 2.5 Hz, 1H; H(6B)), 2.24-2.35 (m, 2H; H(11A), H(16A)), 1.92-2.07 (m, 4H; H(16A), H(7A), H(7b), H(11B)), 1.69-1.87 (m, 4H; H(22A), H(20), H(12A), H(12B)), 1.75 (d,7 = 0.9 Hz, 3H; C(10)-Me), 1.53-1.64 (m, 1H; H(22B)), 1.31 (s, 3H; C(8)-Me), 0.82 (s, 3H; C(13)-Me). 13C N M R (CDCI3, 75 MHz): 8 198.0 (C(5)), 163.6 , 158.8, 129.2, 120.3, 73.0, 70.8, 58.6, 58.6, 52.3, 47.1, 38.8, 37.5, 36.2, 35.8, 35.1, 34.3, 30.2, 27.4, 26.6,19.0, 10.8. IR (neat film): 2929, 2870, 2829, 1662 (vc=o), 1625 (vc=c)> 1602 (vc=c), 1449, 1372, 1098 cm - 1 EIMS m/z (rel intensity): 346 ( M + ; 9.6), 331 ((M - C H 3 ) + ; 11.6), 314 (19.2), 299 (29.0), 213 (100). Exact mass calcd for C22H34O3: 346.2508, found 346.2510. Anal. Calcd for C22H34O3: C, 76.26; H, 9.89. Found: C, 76.31; H, 9.91. Table 5.18. Results of NOE Experiments for Tricyclic Enone 257. Proton Irradiated (ppm) Assignment NOE Correlations (ppm) Assignments** 5.41-5.48 H(15) 2.24-2.35 (U), 1.92-2.07 (part of multiplet), 1.31 H(16), C(8)-Me 1.31 C(8)-Me 5.41-5.48,2.50-2.65 (U), 2.39,1.92-2.07 (part of multiplet) H(15),H(6) 0.82 C(13)-Me 3.30-3.38,3.32,3.29,1.92-2.07 (part of multiplet), 1.69-1.87 (excluding singlet at 1.75) H(21),-OMe,-OMe, The notations (D) and (U) refer to the downfield and upfield parts of multiplets, respectively, whose chemical shifts are given. Only those protons that can be assigned unambiguously have been recorded. 188 Table 5.19. Spectral Data from COSY Spectrum of Tricyclic Enone 257. 400 MHz lH NMR Spectrum Signal Positions [8 (ppm)] Assign-ment COSY Correlations* Signal Positions [8 (ppm)] Assign-ment 5.41-5.48 H(15) 2.24-2.35 (U), 1.92-2.07 H(16A, 16B), 3.44 H(23A) 1.53-1.64,1.69-1.87 H(22A, 22B) 3.42 H(23B) 1.53-1.64,1.69-1.87 H(22A, 22B) 3.38 H(21A) 1.69-1.87 H(20) 3.30-3.35 H(21B) 1.69-1.87 H(20) 2.50-2.65 (D) H(17) 1.69-1.87,2.24-2.35 (U) H(20), H(16A) 2.50-2.65 (U) H(6A) 1.92-2.07,2.39 H(6B, 7A, 7B) 2.39 H(6B) 2.50-2.65 (U), 1.92-2.07 H(6A , 7A, 7B) 2.24-2.35 (D) H(11A) 1.92-2.07, 1.69-1.87 H(11 B . 12A.B) 2.24-2.35 (U) H(16A) 5.41-5.48, 2.50-2.65 (D), 1.69-1.87 H(15),H(17), H(16B) 1.92-2.07 H(16B), H(11B), H(7A,7B) 5.41-5.48,2.50-2.65 (U), 2.39, 2.24-2.35 (D), 1.69-1.87, 1.31 H(15), H(6A), H(6B), H(11A) H(12A, 12B), C(10)-Me 1.69-1.87; 1.75 H(22A), H(20), H(12 A 3 ) C(10)-Me 3.44, 3.42, 3.38, 3.30-3.35 2.50-2.65 (D), 2.24-2.35 (U), 1.92-2.07, 1.53-1.64 H(23A, 23B), H(17,21A,21B) H ( 1 1 A , H B ) . H(22B) 1.53-1.64 H(22B) 3.44, 3.42, 1.69-1.87 (U) H(23A, 23B) H(20) 1.31 C(10)-Me 1.92-2.07 (U) H(11B) *The notations (D) and (U) refer to the downfield and upfield parts of the multiplet whose chemical shift range is given. 189 (-)-2-MethyIenebornane (88)72 O; C H 3 - P P h 3 + B r , BuLi THF, reflux ^8 9 88 To a suspension of methyltriphenylphosphonium bromide (154.7 g, 0.4330 mol) in THF (400 mL) was added «-butyllithium (307 mL, 1.55 M in hexane, 0.476 mol) dropwise over 0.5 h. The resulting red-orange solution was stirred at 50 °C for 2 h, and then allowed to cool to room temperature. A solution of (+)-camphor (9; 41.2 g, 0.271 mol) in THF (160 mL) was added dropwise over 0.5 h. The reaction mixture was refluxed for 12 h and allowed to cool to room temperature. The volume of the reaction mixture was reduced to -300 mL by rotary evaporation and then poured into water (300 mL). The organic layer was removed while the aqueous layer was extracted with pet. ether (3 x 200 mL). The combined organic layers were washed successively with water (1 x 500 mL) and brine (3 x 500 mL), dried over anhydrous MgSC>4, and concentrated under reduced pressure to yield a white slush. Further purification by flash column chromatography [100% pet. ether] provided 2-methylenebornane (88) as a volatile, white, waxy solid (55.4507 g, 85%); mp 69.5-71.0 °C {lit?1 mp 68-70 °C). ! H N M R (CDC1 3 , 400 MHz): 8 4.69 (bs, 1H; = C H A H b ) , 4.61 (dd, / = 3.0, 2.0 Hz, 1H; =CHAHB), 2.38 (bd, / = 16.0 Hz, 1H; H(3 e m)), 1.91 (dt, J =16.0, 1.5 Hz, 1H; H(3endo)), 1.68-1.80 (m, 2H; H(5 e m ) , H(4)), 1.64 (ddd, J = 11.9, 11.9, 3.6 Hz, 1H; H(6ex0)), 1.16-1.30 (m, 2H; H(5endol H(6endo)), 0.92 (s, 3H; H(9)), 0.89 (s, 3H; H(10)), 0.76 (s, 3H; H(8)). 13C N M R (CDCI3,75 MHz): 8 159.2 (C(2)), 101.2 (=CH 2 ) , 51.4,47.2, 44.8, 37.0, 35.2,28.0, 19.6,19.0,12.5. IR (CHCI3) : 2900,2875,1652 (v c = c), 1472,1448,1382,1365, 878 cm-1 EIMS mlz (rel intensity): 150 ( M + ; 10.2), 135 ((M - C H 3 ) + ; 8.6), 69 (80.6), 55 (26.9). 190 Exact mass calcd for CnHig : 150.1409, found 150.1413. Anal. Calcd for C n H is: C, 87.93; H, 12.07. Found: C, 87.71; H, 12.10. (+)-4-MethylisobornyI acetate (89)72 88 HOAc, H2S04 OAc To a solution of 2-methylenebornane (88; 28.6912 g, 0.1909 mol) in glacial acetic acid (125 mL) was added concentrated sulfuric acid (3.0 mL) dropwise over -1-2 min. The colorless solution was stirred for 30 min and then diluted with Et20 (-150 mL) and poured into water (150 mL). The organic phase was withdrawn while the aqueous phase was extracted with Et20 (2 x 100 mL). The combined extracts were washed with water (3 x 150 mL), neutralized with saturated aq. NaHC03 (3 x 150 mL), and washed with brine (3 x 150 mL). After the organic layer was dried over anhydrous MgS04, the solvent was removed by rotary evaporation to yield 4-methylisobornyl acetate (89) as a volatile, clear, colorless liquid (33.4923 g, 83%) that could be used directly in the subsequent step. However, further purification of the product acetate 89 could be accomplished by flash column chromatography [5% Et20-pet. ether]. 1H N M R (CDC1 3 , 400 MHz) : 8 4.65 (dd, J = 11.5, 7.8 Hz, 1H; H(2)), 2.01 (s, 3H; -C(0)CH3), 1.82 (dd, 18.0, 7.8 Hz, 1H; H(3exa)), 1.36-1.54 (m, 3H; HQendo), H(5eXol H(6exo)), 1.10-1.19 (m, 2H; H(5endo), mendo)\ 0.90 (s, 3H; H(4')), 0.86 (s, 3H; H(10)), 0.83 (s, 3H; H(8)), 0.70 (s, 3H; H(9)). « C N M R (CDCI3, 50 MHz): 8 170.5 (C=0), 80.0 (C(2)), 50.4, 47.7, 46.8, 45.4, 34.3, 33.1, 21.2, 17.6, 17.5, 15.6,12.0. IR (neat film): 2955,2855,1740 (vC=oX 1458,1362,1242,1040 cm-1 191 EIMS m/z (rel intensity): 210 ( M + ; 2.0), 150 (50.9), 135 (48.3), 109 (82.3), 43 ( C H 3 O 0 + ; 100). Exact mass calcd for C13H22O2: 210.1620, found 210.1622. Anal. Calcd for C13H22O2: C, 74.24; H, 10.54. Found: C, 74.82; H, 10.70. (+)-4-Methylisoborneol (90)72 To a suspension of lithium aluminum hydride (12.0869 g, 0.3185 mol) in THF (250 mL) at 0 °C was added, dropwise over 20 min, a solution of 4-methylisobornyl acetate (89; 33.4923 g, 0.1592 mol) in THF (100 mL). The reaction mixture was stirred at 0 °C for 5 h. The reaction was then quenched by cautious, dropwise addition of water (-100 mL). The quenched mixture was stirred for a further hour, then diluted with a further aliquot of water (-100 mL). The pasty white solid in the reaction mixture was dissolved by cautious, dropwise addition of 6 M HCl (-10 mL). The aqueous solution was then extracted with Et20 (3 x 100 mL). The combined organic extracts were washed successively with water (2 x 300 mL), neutralized with saturated aq. NaHC03 (2 x 500 mL), washed with brine (3 x 300 mL), dried over anhydrous MgSCU, and concentrated to yield 4-methylisoborneol (90) as a white solid (26.0655 g, 97%) that could be used directly in the next reaction. Further purification could be accomplished by flash column chromatography [60% Et20-pet. ether]; mp 193.5-195.0 °C (lit?2 195-196.5 °C; .193-194 °C). 1H N M R (CDCI3,400 MHz): 8 3.59 (dd,7= 11.7,4.9 Hz, 1H; H(2)), 1.74 (dd,/= 18.6, 11.7 Hz, 1H; H(3ex0)), 1.58 (bs, 1H; exchanges with D 2 0 ; -OH), 1.34-1.55 (m, 3H), 0.98-89 90 192 1.15 (m, 2H), 0.96 (s, 3 H ; H(4')), 0.92 (s, 3 H ; H(10)), 0.89 (s, 3 H ; H(8)), 0.68 (s, 3 H ; H(9)). 13C N M R (CDC1 3,75 MHz): 8 78.7 (C(2)), 50.8,47.1,46.6, 34.5, 33.3,18.0,17.8,15.8,12.0. IR ( C H C I 3 ) : 3420 (VO-H), 2960,2890,1460,1040 cnr* EIMS mlz (rel intensity): 168 ( M + ; 2.1), 150 ( ( M - H 2 0 ) + ; 14.4), 109 (100), 41 (70.6). Exact mass calcd for C11H20O: 168.1514, found 168.1514. Anal. Calcd for C11H20O: C, 78.51; H, 11.98. Found: C, 78.57; H , 11.99. (_)-4-Methylcamphor (87)72 To a solution of 4-methylisoborneol (90; 30.4403 g, 0.1809 mol) in acetone (75 mL) at 0 °C was added, dropwise over 20 min, Jones reagent [prepared from chromium(VI) oxide (18.09 g, 0.1809 mol), water (40 mL), and concentrated sulfuric acid (10 mL)]. The dark orange-green reaction mixture was stirred at 0 °C for 2 h after which saturated aq. NaHS03 (-20 mL) was added. The reaction mixture was poured into water (-200 mL) and extracted with Et20 (3 x 100 mL). The organic extracts were washed with water (4 x 250 mL), neutralized with saturated aq. NaHC03 (2 x 250 mL), washed with brine (3 x 250 mL), dried over anhydrous MgS04, and concentrated under reduced pressure to yield 4-methylcamphor (87) as a volatile, white solid (29.6423 g, 99%) that could be used directly in the next reaction. Further purification could be accomplished by flash column chromatography [5% Et20-pet. ether]; mp 160-162 °C (lit?2 167-168 ° C ) . 193 ! H N M R (CDCI3, 400 MHz): 8 2.06 (dd, J = 18.1, 3.0 Hz, 1H; H(3exo), 1.85 (d, J = 18.1 Hz, 1H; H(3endo)), 1.57-1.73 (m, 2H), 1.33-1.42 (m, 2H), 1.02 (s, 3H; H(4')), 0.90 (s, 3H; H(10)), 0.81 (s, 3H; H(9)), 0.69 (s, 3H; H(8)). !3C N M R (CDCI3, 75 MHz): 8 219.3 (C(2)), 59.7, 49.0, 48.1, 45.5, 34.3, 29.6, 17.5, 15.8, 15.5, 10.1. IR (CHCI3): 2970, 2895,1735 (vc=o), 1418,1381 cnr* EIMS mlz (rel intensity): 166 ( M + ; 39.8), 138 (13.9), 109 (94.8), 83 (19.6), 82 (100). Exact mass calcd for C n H i 8 0 : 166.1358, found 166.1360. Anal. Calcd for C i i H i 8 0 : C, 79.47; H, 10.91. Found: C, 79.67; H, 11.03 enrfo-3-Bromo-4-methylcamphor (327)72 To a solution of 4-methylcamphor (327; 27.6423 g, 0.1663 mmol) in glacial acetic acid (250 mL) at 80 °C was added, dropwise over 30 min, a solution of bromine (9.4 mL, 29 g, 0.18 mmol) in glacial acetic acid (10 mL). The red-orange solution was stirred at 80 °C for 18 h, allowed to cool to room temperature, and poured cautiously into a saturated aq. NaHS03 solution (-100 mL). The aqueous solution was decanted and extracted with Et20 (2 x 250 mL) while the precipitated crude product was dissolved in Et20 (250 mL). The combined organic solutions were washed with water (2x1 L), neutralized with saturated aq. NaHC03 (3 x 500 mL), washed with brine (3 x 500 mL), dried over anhydrous MgS04, and concentrated under reduced pressure to a light orange-brown solid. Recrystallization of the orange-brown solid from methanol yielded e«rfo-3-bromo-4-methylcamphor as white crystals (24.8824 g, 61%). Subsequent purification of the mother liquor by flash column chromatography [10% Et20-pet. 87 327 Br 194 ether] yielded a minor by-product 3,3-dibromo-4-methylcamphor (369; 1.2241 g) and upon further elution, endo-3-bromo-4-methylcamphor (327; 14.2946 g, 35%; total yield 96%) as a volatile, white solid; mp 119.5-121.5 °C (lit.12 119.5-120.5 °C). cndo-3-Bromo-4-methylcamphor (327) ! H N M R (CDC13,400 MHz): 8 4.28 (d, J = 1.4 Hz, 1H; H(3exo)\ 2.00-2.10 (m, 1H; H(5exo)), 1.48-1.67 (m, 2H), 1.33-1.42 (m, 1H), 1.03 (s, 3H; H(4')), 0.97 (s, 3H; H(10)), 0.95 (s, 3H; H(9)), 0.78 (s, 3H; H(8)). 1 3 C N M R (CDCI3, 75 MHz): 8 212.3 (C(2)), 60.4 (C(3)), 59.0, 50.8, 47.0, 30.1, 29.1, 17.4, 17.1, 13.8, 10.2. IR (CHCI3): 2960, 2925, 2880,1747 (vc=o), 1451, 1396 cm-1 EIMS mlz (rel intensity): 246/244 ( M + ; 5.0/4.9), 165 ((M - Br) + ; 48.1), 137 (52.1), 123 (45.0), 109 (75.7). Exact mass calcd for C i i H n 7 9 B r O : 244.0462, found 244.0467. Exact mass calcd for C i i H n ^ B r O : 246.0442, found 246.0439. Anal. Calcd for C n H n B r O : C, 53.89; H, 6.99. Found: C, 53.59; H, 7.02. 3.3 -Dibromo-4-methylcamphor (369) * H N M R (CDCI3, 200 MHz): 8 2.29-2.44 (m, 1H), 1.80-2.04 (m, 1H), 1.50-1.64 (m, 2H), 1.30 (s, 3H), 1.05 (s, 3H), 1.02 (s, 3H), 0.99 (s, 3H). EIMS mlz (rel intensity): 326/324/322 ( M + ; 2.6/5.9/2.9), 245/243 ((M - Br) + ; 30.9/31.1). Exact mass calcd for C i i H i 6 7 9 B r 7 9 B r O : 321.9567, found 321.9570. Exact mass calcd for C i i H ^ B r ^ B r O : 323.9547, found 323.9552. Exact mass calcd for C i i H i ^ B r ^ B r O : 325.9527, found 325.9525. 195 enrfo-3,9-Dibromo-4-(bromomethyI)camphor (332) 7 2 .0 Br2 (2.2 eq), C1S03H Br Br >r Br 332 .0 To a 250-mL, single-neck, round-bottom flask containing endo-3-bromo-4-methyl-camphor (327; 24.8824 g, 0.1015 mmol) and immersed in an ice-water bath was added in rapid succession chlorosulfonic acid (20 mL) and bromine (12.0 mL, 37.3 g, 0.233 mmol). The solution was stirred at 0 °C for 10 min and then at room temperature for 18 h. The reaction mixture was poured cautiously onto ice (~200 mL) and saturated aq. NaHSO"3 (100 mL) was added slowly. The aqueous mixture was extracted with dichloromethane or chloroform (5 x 100 mL). The organic extracts were washed with water (5 x 500 mL), neutralized with saturated aq. NaHCO-3 (3 x 250 mL), washed with brine (3 x 250 mL), dried over anhydrous MgSQ*, and concentrated under reduced pressure to yield a yellow-brown solid. Subsequent purification of the solid by recrystallization [4:5 MeOH -CHCl3; 90 mL] yielded pure e«do-3,9-dibromo-4-(bromomethyl)camphor (332; 22.4142 g, 55%). The mother liquor was purified further, in two batches, by flash column chromatography (15% Et20-pet. ether) to yield the by-products, endo-3,9-dibromo-4-methylcamphor (328; 0.5897 g), enofo-3,9,9-tribromo-4-(bromomethyl)camphor ( 3 7 0 ; 0.5779 g), and upon further elution, the desired mfo-3,9-dibromo-4-(bromomethyl)camphor (332; 12.0203 g, 29%; total yield 84%) as a white solid; mp 142.0-143.0 °C (lit72 142.5-143.5 °C). endo-i .9-dibromo-4-(bromomethvl)camphor (332) 1H N M R (CDCI3, 400 MHz): 8 4.92 (d, J = 2.3 Hz, 1H; H(3 e m)), 4.06 (d, J = 11.6 Hz, 1H; H(4'A)), 3.74 (d, J = 11.0 Hz, 1H; H(9A)), 3.52 (d, / = 11.6 Hz, 1H; H(4 ,B)), 3.46 (d, / = 11.0 Hz, 1H; H(9B)), 2.19 (ddd, J = 13.5, 9.7, 4.0 Hz, 1H; H(5endo)), 1.82 (dddd, / = 196 13.5, 13.5, 5.0, 2.3 Hz, 1H; U(5exo), 1.70 (ddd, 7 = 13.5, 13.5, 3.9 Hz, 1H; U(6exo)), 1.52 (ddd, J = 13.5, 9.7, 5.0 Hz, 1H; U(6endo)), 1-24 (s, 3H; H(8)), 1.03 (s, 3H; HQO)). N M R (CDC1 3, 75 MHz): 5 208.6 (C(2)), 61.1, 55.4, 54.2, 50.6, 35.8, 31.3, 29.6, 28.2, 16.7, 10.4. IR (CHCI3): 2924, 2935,2850,1745 (v c = o), 1456,1425,1396, 1380, 1256 cm"1 EIMS mlz (rel intensity): 406/404/402/400 ( M + ; 0.4/1.8/2.0/0.7), 325/323/321 ((M - Br) + ; 17.1/41.7/18.8), 245/243 ((M - 2Br)+; 14.0/18.8), 201/199 (28.7/22.2). Exact mass calcd for CnHi5 79Br79Br 79BrO: 399.8672, found 399.8675. Exact mass calcd for C n H i s ^ B r ^ B r ^ B r O : 401.8652, found 401.8667. Exact mass calcd for CnHi579Br8lBr8lBrO: 403.8632, found 403.8637. Exact mass calcd for C i iHi 5 8 1 Br8lBr8 lBrO: 405.8612, found 405.8605. Anal. Calcd for C n H i 5 B r 3 0 : C, 32.79; H, 3.75. Found: C, 33.05; H, 3.78. endo-3.9-dibromo-4-methylcamphor (328) 1H N M R (CDCI3, 400 MHz): 8 4.28 (bs, 1H; H(3e^)), 3.54 (d, J = 9.9 Hz, 1H; H(9A)), 3.46 (d, / = 9.9 Hz, 1H; H(9B)), 2.01-2.17 (m, 1H), 1.57-1.68 (m, 2H), 1.33-1.42 (m, 1H), 1.12 (s, 3H; H(4')), 1.02 (s, 3H; H(10)), 0.98 (s, 3H; H(8)). 13C N M R (CDCI3,75 MHz): 8 209.3 (C(2)), 60.1 (C(l)), 59.8 (C(3)), 52.2, 49.5, 36.6 (C(9)), 29.8, 29.0,15.3,15.1,11.3. Exact mass calcd for C i i H i 6 7 9 B r 7 9 B r O : 321.9567, found 321.9564. Exact mass calcd for C n H i e ^ B r ^ B r O : 323.9547, found 323.9552. Exact mass calcd f o r C n H i e ^ B r ^ B r O : 325.9527, found 325.9529. endo-3.9.9-Tribromo-4-(bromomethvl)camphor (370) l H N M R (CDC13,400 MHz): 8 6.28 (s, 1H; H(9)), 5.05 (d, J = 0.7 Hz, 1H; H(3)), 4.19 (d, J = 10.5 Hz, 1H; H(4'A)), 3.47 (d,7 = 10.5 Hz, 1H; H(4'B)), 2.10-2.21 (m, 2H), 1.71-1.85 (m, 2H), 1.49 (s, 3H; H(8)), 1.24 (s, 3H; H(10)). EIMS m/z (rel intensity): 486/484/482/480/478 ( M + ; 0.4/2.1/3.2/2.2/0.5),. Exact mass calcd for C i i H i 4 7 9 B r 7 9 B r 7 9 B r 7 9 B r O : 477.7777, found 477.7780. Exact mass calcd for C n H i 4 7 9 B r 7 9 B r 7 9 B r « l B r O : 479.7757, found 479.7761. Exact mass calcd for C n H i 4 7 9 B r 7 9 B r 8 l B r 8 l B r O : 481.7737, found 481.7745. Exact mass calcd for C n H i ^ B r ^ B ^ B r ^ B r O : 483.7717, found 483.7722. Exact mass calcd for C n H i 4 8 l B r 8 l B r 8 l B r 8 l B r O : 485.7697, found 384.7704. Table 5.20. Results of NOE Experiments for e«do-3,9-Dibromo-4-(bromomethyl)camphor (332). Proton Irradiated (ppm) Assignment NOE Correlations (ppm) Assignments* 4.92 H(3 e m ) 4.06, 3.52, 1.24 H(4'A, 4'B, 8) 4.06 H(4'A) 4.92,3.52, 2.19, 1.82 H(3, 4'A, $endoi $exo) 3.74 H(9A) 3.46, 1.82,1.70 H(9B, 5exo, 6exo) 2.19 H(5en^o) 4.06, 3.52, 1.82, 1.70, 1.52 H(4'A, 4'B, 5exo), H(6 e ; c 0 , 6endo) 1.52 2.19,1.70, 1.03 H(5 e n d 0 , 6exo, 10) 1.24 H(8) 4.92,3.46, 1.03 H ( 3 « „ , 9 B , 10) 1.03 H(10) 3.46, 1.70,1.52, 1.24 H(9B, 6ex0, 6endO' 8) *Only those protons that can be assigned unambiguously have been recorded. 198 Table 5.21. Spectral Data from COSY Spectrum of e«do-3,9-Dibromo-4-(bromomethyl)-camphor (332). 400 MHz ! H NMR Spectrum Signal Positions [8 (ppm)] Assign-ment COSY Correlations Signal Positions [8 (ppm)] Assignment 4.92 H(3em) 1.82 H(5 e j c o) 4.06 H(4'A) 3.52 H(4'B) 3.74 H(9A) 3.46, 1.24 H(9 B), H(8) 3.52 H(4'B) 4.06 H(4'A) 3.46 H(9B) 3.74 H(9A) 2.19 1.82,1.70,1.52 H(5 e x o ) , H(6gnrfo and exo) 1.82 H(5 e m ) 2.19, 1.70, 1.52 H(5ewrf0), agendo and exo) 1.70 H(6«o) 2.19, 1.82,1.52 H(5endo and exo)-> H(6endo) 1.52 agendo) 2.19,1.82, 1.70 H(5endo and exo\ mexo) 1.24 H(8) 3.74 H(9A) Table 5.22. Spectral Data from HETCOR Spectrum of e/ido-3,9-Dibromo-4-(bromomethyl)-camphor (332). 75 MHz 1 3 C NMR Spectrum Signal Positions [5c (ppm)] Assign-ment HETCOR Correlations Signal Positions [8 H (ppm)] Assign-ment 61.1 C(3) 4.92 HOexo) 35.8 C(4') 4.06, 3.52 H(4') 31.3 C(9) 3.74, 3.46 H(9) 29.6 C(6) 1.70,1.52 H(6) 28.2 C(5) 2.19,1.82 H(5) 16.7 C(8) 1.24 H(8) 10.4 C(10) 1.03 H(10) 199 Attempted Preparation of enrfo-3,9-Dibromo-4-methylcamphor (328) enrfo-3-Bromo-4-methylcarnphor (327; 1.0473 g, 4.2719 mmol) was dissolved at 0 °C in chlorosulfonic acid (2.0 mL) and bromine (0.3 mL, 0.8 g, 5 mmol) was added immediately. The solution was stirred at room temperature for 5 h. The reaction mixture was worked up according to the procedure outlined on p. 195. Subsequent purification of the solid by flash column chromatography [15% Et20-pet. ether] yielded as the major products emfo-3,9-dibromo-4-methylcamphor (328; 0.5511 g) and £rtdo-3,9-dibromo-4-(bromomethyl)camphor (332; 0.5707 g), the spectral characteristics of both were in accordance with those obtained previously (see pp. 195-6). Conversion of endo-3,9-Dibromo-4-methylcamphor (328) to <?/ufo-3,9-Dibromo-4-(bromo-methyl)camphor (332) endo-3,9-Dibromo-4-methylcamphor (328; 0.5274 g, 1.628 mmol) was dissolved in a solution of bromine (0.1 mL, 0.3 g, 2 mmol) in chlorosulfonic acid (1.0 mL) and was stirred at room temperature for 1 h. Work-up and purification of the product according to methods outlined on p. 195 yielded e«do-3,9,9-tribromo-4-(bromomethyl)camphor (370; 0.0959 g) and e«do-3,9-dibromo-4-(bromomethyl)camphor (332; 0.4162 g, 63%), whose 400 MHz lH NMR spectral characteristics were identical to those presented previously (see pp. 195-6). 200 9-Bromo-4-(bromomethyl)camphor (362)72 To a cloudy, ice-cold solution of ertrfo-3,9-dibromo-4-(bromomethyl)camphor (332; 22.4142 g, 55.62 mmol) in 1:1 glacial acetic acid-Et20 (500 mL) at 0 °C was added zinc dust (7.2735 g, 111.2 mmol) in ~5 portions over 15-20 min, such that the temperature of the reaction mixture did not exceed 10 °C. The reaction mixture was stirred at 0 °C for 1 h after which it was filtered through a Celite® pad. The Celite® pad was washed further with Et20 (200 mL). The filtrate was then washed with water (4 x 250 mL), neutralized with saturated aq. NaHC03 (3 x 500 mL), washed with brine (3 x 500 mL), dried over anhydrous MgS04, and concentrated to a light brown solid. The crude solid was triturated in ice-cold methanol (~ 15-20 mL) to yield pure 9-bromo-4-(bromomethyl)camphor (362, 8.0775 g, 45%) as white crystals. Subsequent purification of the mother liquor by flash column chromatography [20% Et20-pet. ether] yielded a further quantity of pure 9-bromo-4-(bromomethyl)camphor (362; 6.4791 g, 36%; total yield 81%) as a white solid; mp 54.0-55.0 °C (lit.72 53-55 °C). ! H N M R (CDC13,400 MHz): 5 3.95 (d, J = 10.3 Hz, 1H; H(4'A)), 3.61 (dd, J = 11.0,0.6 Hz, 1H; H(9A)), 3.57 (d, / = 10.3 Hz, 1H; H(4'B)), 3.30 (d, J = 11.0 Hz, 1H; H(9B)), 2.29 (dd, / = 8.5, 2.6 Hz, 1H; H(3exo)), 2.26 (d, / = 8.5 Hz, 1H; H(3endo)), 1.82-1.96 (m, 2H), 1.65-1.75 (m, 1H), 1.43-1.53 (m, 1H), 0.99 (s, 3H; H(8)), 0.95 (s, 3H; HQO)). 13C N M R (CDCI3, 75 MHz): S 213.4 (C(2)), 61.9, 52.0, 51.3, 47.7, 36.1, 35.8, 31.8, 28.4, 15.3,10.6. IR (CHCI3): 2960,2925,2838,2829,1743 (vC=o), 1458,1425,1378,1319,1248 cm"1 201 EIMS mlz (rel intensity): 326/324/322 ( M + ; 11.4/23.9/12.7), 245/243 ((M - B r ) + ; 56.2/56.2), 217/215 (35.5/35.2), 201/199 (83.9/76.6), 163(50.3). Exact mass calcd for C i i H i 6 7 9 B r 7 9 B r O : 321.9567, found 321.9585. Exact mass calcd for C n H i 6 7 9 B r 8 l B r O : 323.9547, found 323.9543. Exact mass calcd for C n H i 6 8 1 B r 8 l B r O : 325.9527, found 325.9532. Anal. Calcd for C n H i 6 B r 2 0 : C, 40.77; H, 4.98. Found: C, 40.96; H, 5.01. 9-Deuterio-4-(deuteriomethyl)camphor (363)72 To a solution of 9-bromo-4-(bromomethyl)camphor (362; 3.0525 g, 9.4196 mmol) in dry benzene (70 mL) was added AIBN (0.3313 g, 2.018 mmol) and then tributyltin deuteride (6.2 mL, 6.7 g, 23 mmol) in three portions. The reaction mixture was refluxed for 17 h after which it was cooled to room temperature. Methanol (50 mL) was added and the combined solvents were removed under reduced pressure to produce the crude product as a pale yellow slush. Purification by flash column chromatography (1.5% Et20-pet. ether) provided 9-deuterio-4-(deuteriomethyl)camphor (363) as slushy, volatile, white crystals (1.2143 g, 58%) 1H N M R (CDC13,400 MHz): 8 2.07 (dd, J = 18.2, 3.0 Hz, 1H; HQex0), 1.85 (d, J = 18.2 Hz, 1H; H(3end0)), 1.57-1.73 (m, 2H), 1.32-1.42 (m, 2H), 1.00 (t, J = 1.9 Hz, 2H; H(4')), 0.90 (s, 3H; H(10)), 0.80 (t, / = 1.9 Hz, 2H; H(9)), 0.69 (s, 3H; H(8)). " C N M R (CDCI3 ,7 5 MHz): 8 218.9, 59.4,48.7,47.8, 45.2, 34.0, 29.4, 17.2, 15.3 (t, 7„ c , H = 19.0 Hz), 14.9 (t, 7Uc_,H = 18.9 Hz), 9.9. IR ( C H C I 3 ) : 2970,2895,1735 (vC=oX 1418,1381 cm-l 362 363 202 EIMS m/z (rel intensity): 168 (M+; 56.0), 140 (19.3), 124 (75.2), 111 (67.4), 96 (21.5), 84 (100). Exact mass calcd for C n H i 6 D 2 0 : 168.1481, found 168.1483. Table 5.23. Spectral Data from COSY Spectrum of 9-Deuterio-4-(deuteriomethyl)camphor (363). 400 MHz ! H NMR Spectrum Signal Positions [8 (ppm)] Assign-ment COSY Correlations Signal Positions [8 (ppm)] Assign-ment 2.07 H(3exo) 1.85,1.57-1.73 (part of multiplet) hlQendO' 5exo) 1.85 HO endo) 2.07 1.57-1.73 H(5 e m ) H(6A) 2.07,1.32-1.42 H(3 e x o , 6B) 1.32-1.42 H(5e/j<fo), H(6B) 1.57-1.73 H(5 e m ) , H(6A) 0.80 H(9) 0.69 H(8) 0.69 H(8) 0.80 H(9) enrfo-3-Bromo-9-deuterio-4-(deuteriomethyl)camphor (351) To a solution of 9-deuterio-4-(deuteriomethyl)camphor (363) (1.1587 g, 6.8857 mmol) in glacial acetic acid (4.5 mL) was added a solution of bromine (1.5 mL, 4.8 g, 15 mmol) in glacial acetic acid (1.5 mL). The reaction mixture was heated at 80 °C for 18 h and was then poured into ice-cold, saturated aqueous sodium bisulfite solution (20 mL). The aqueous mixture was extracted with Et 2 0 (3 x 25 mL) and the combined extracts washed successively with saturated aq. NaHS03 (1 x 50 mL), NaHC0 3 (3 x 50 mL), water (4 x 50 mL), and brine (2 x 50 mL). The organic solution was then dried over anhydrous M g S 0 4 and concentrated under reduced 203 pressure to provide a viscous brown syrup. Subsequent purification by flash column chromatography (5% Et20-pet. ether) yielded end<?-3-bromo-9-deuterio-4-(deuteriomethyl)camphor (351) as white crystals (0.8125 g, 48%). 1H N M R (CDC13,400 MHz): S 4.28 (d, J = 1.4 Hz, 1H; HQexo)), 2.00-2.10 (m, 1H; H(5exo)\ 1.48-1.67 (m, 2H), 1.33-1.42 (m, 1H), 0.99 (t, J = 1.9 Hz, 3H; H(4')), 0.97 (s, 3H; H(10)), 0.95 (t, J = 1.9 Hz, 3H; H(9)), 0.78 (s, 3H; H(8)). 13C N M R (CDCI3, 75 MHz): 8 212.3 (C(2)), 60.4, 59.0, 50.8, 47.0, 30.1, 29.1, 17.4, 16.9 (t, 7llc_,H = 19.0 Hz), 13.5 (t, 7IJc_,H = 19.3 Hz). EIMS mlz (rel intensity): 248/246 ( M + ; 11.0/11.6), 167 ( ( M - B r ) + ; 100), 139 (90.9). Exact mass calcd for C i i H i 5 7 9 B r D 2 0 : 246.0586, found 246.0596. Exact mass calcd for C i i H i 5 8 1 B r D 2 0 : 248.0566 found 248.0573. e/ido-3,9-Dibromo-9-deuterio-4-(bromodeuteriomethyl)camphor (352) D 351 352 To an ice-cold solution of ertrfo-3-bromo-9-deuterio-4-(deuteriomethyl)camphor (351; 1.6246 g, 6.5727 mmol) in chlorosulfonic acid (5.0 mL) was added bromine (0.76 mL, 2.4 g, 15 mmol) in one portion. The reaction mixture was stirred at 0 °C for 1 min and at room temperature for 15 h and then poured cautiously onto ice (~25 mL) containing saturated aq NaHSC»3 solution (-25 mL). The precipitated solid was collected by suction filtration, re-dissolved in diethyl ether (100 mL), and then washed successively with saturated aq. NaHSC»3 (1 x 50 mL), neutralized with saturated aq. NaHCC>3 (3 x 100 mL), and washed with brine (3 x 100 204 mL). Solvent removal under reduced pressure yielded crude product as an off-white powder. Subsequent purification by flash column chromatography (15% Et20—pet. ether) provided endo-3,9-dibrbmo-9-deuterio-4-(bromodeuteriomethyl)camphor (352) as colorless needles (0.9845 g, 63%). 1H N M R (CDCI3, 400 MHz): S 4.92 (d, J = 2.3 Hz, 1H; H(3 e m)), 4.01/3.48 (bs, 1H; H(4')), 3.70/3.41 (bs, 1H; H(9)), 2.19 (ddd, / = 13.5, 9.7, 4.0 Hz, 1H; H(5 e n d o)), 1.82 (dddd, J = 13.5, 13.5, 5.0, 2.3 Hz, 1H; U(5exo), 1.70 (ddd, 7 = 13.5, 13.5, 3.9 Hz, 1H; U(6exo)), 1.52 (ddd, J = 13.5, 9.7, 5.0 Hz, 1H; B(6endo)l 1-24 (s, 3H; H(8)), 1.03 (s, 3H; H(10)). 1 3C N M R (CDCI3, 75 MHz): <5 208.0, 61.1, 55.4, 54.1, 50.4, 35.7 (t, 7„ r 2 u = 23.5 Hz), 31.1 (t, 713r 2 u = 23.4 Hz), 29.6, 28.2,16.7, 10.4. EIMS mlz (rel intensity): 408/406/404/402 ( M + ; 1.4/4.5/5.8/2.2), 327/325/323 ((M - Br) + ; 47.8/100/52.8), 299/297/295 (4.6/10.7/5.4). Exact mass calcd for C n H i 3 7 9 B r 7 9 B r 7 9 B r D 2 0 : 401.8795, found 401.8778. Exact mass calcd for CiiHi 3 7 9 B r 7 9 B r 8 1 B r D 2 0 : 403.8775, found 403.8782. Exact mass calcd for C n H i 3 7 9 B r 8 1 B r 8 1 B r D 2 0 : 405.8755, found 405.8763. Exact mass calcd for Ci i H r s ^ B r ^ B r ^ B r D ^ : 407.8735, found 407.8748. 9-Bromo-9-deuterio-4-(bromodeuteriomethyl)camphor (364) D D Zn, l:lHOAc-Et2O,0°C To a solution of eAirfo-3,9-dibromo-9-deuterio-4-(bromodeuteriomethyl)camphor (352; 0.9375 g, 2.315 mmol) in 2:1 H O A c - E t 2 0 (6.0 mL) at 0 °C was added zinc dust (0.3813 g, 205 5.832 mmol) in one portion. The reaction was allowed to proceed at 0 °C for 3.0 h. Solid materials in the reaction mixture were removed by filtration. The filtrate was diluted with Et20 (-100 mL), washed successively with water (3 x 50 mL), saturated aqueous NaHC03 (1 x 50 mL), and brine (2 x 50 mL), and dried over anhydrous MgSC>4. Removal of solvent under reduced pressure yielded a golden-yellow product that was purified further by radial chromatography (2 mm plate; 5% Et20-pet. ether or 2.5% EtOAc-pet. ether) to yield 9-bromo-9-deuterio-4-(bromodeuteriomethyl)camphor (364) as a white solid (0.6115 g, 82%). * H N M R (CDCI 3,400 MHz): 8 3.90/3.53 (bs, 1H; H(4')), 3.56/3.26 (bs, 1H; H(9)), 2.29 (dd, J = 8.5, 2.6 Hz, 1H; U(3exo)), 2.26 (d,7 = 8.5 Hz, 1H; UOendo)), 1.82-1.96 (m, 2H), 1.65-1.75 (m, 1H), 1.43-1.53 (m, 1H), 0.99 (s, 3H; H(8)), 0.95 (s, 3H; H(10)). 1 3 C N M R (CDCI3, 75 MHz): 8 212.9 (C(2)), 61.6, 51.7, 50.9, 47.4, 35.8 (t, 7 U „ , = 19.1 H Hz), 35.6 (t, 7IS_ ,„ = 21.4 Hz), 31.6, 28.1, 15.1, 10.4. C — H EIMS mlz (rel intensity): 328/326/324 (M+; 18.5/38.4/21.0), 284/282/280 (10.6/22.2/12.1), 247/245 ((M - Br) +; 87.7/93.2). Exact mass calcd for C n H i 4 7 9 B r 7 9 B r D 2 0 : 323.9691, found 323.9684. Exact mass calcd for CnHi4 7 9 Br 8 1 BrD20 : 325.9671, found 325.9677. Exact mass calcd for C n H i 4 8 1 B r 8 1 B r D 2 0 : 327.9651, found 327.9640. 1 206 Debromination of 9-Bromo-9-deuterio-4-(bromodeuteriomethyl)camphor (364) to Yield 9-Deuterio-4-(deuteriomethyl)camphor (363). To a solution of 9-bromo-9-deuterio-4-(bromodeuteriomethyl)camphor (364; 101 mg, 0.310 mmol) in dry benzene (5.0 mL) was added AIBN (0.110 g, 66.7 ^mol). and then tributyltin hydride (205 pL, 221 mg, 0.759 mmol). The reaction mixture was refluxed for 2 h after which it was cooled to room temperature. The solvent was removed under reduced pressure to yield an oily residue that was purified directly by flash column chromatography (1.5% Et20—pet. ether) to afford 9-deuterio-4-(deuteriomethyl)camphor (363) as white crystals (33.5 mg, 64%). D D 363 363 References and Notes 208 References and Notes 1. Carroll, L. Through the Looking-Glass, and What Alice Found There; Legacy: New York, 1966; p 10. 2. (a) Gaffield, W. 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For alternative syntheses of (±)-pyroangolensolide (246), see: (a) Bentley, M.D.; Rajab, M.S.; Mendel, M.J.; Alford, A.R. J. Agric. Food Chem. 1990,38, 1400. (b) Liu, H.-J.; Dieck-Abularach, T. Heterocycles 1987,25, 245. (c) cf. Davis, J.B.; Godfrey, V . M . ; Jewers, K.; Manchanda, A . H . ; Robinson, F.V.; Taylor, D.A.H. Chem. Ind. (London) 1970, 201. (d) cf. Jewers, K.; Manchanda, A.H. ; Taylor, D.A.H. Chem. Ind. (London) 1972, 976. 128. Renoud-Grappin, M . ; Vanucci, C ; Lhommet, G. J. Org. Chem. 1994,59, 3902. 129. (a) Joule, J.A.; Mills, K.; Smith, G.F. Heterocyclic Chemistry, 3rd ed:, Chapman & Hall: London, 1995; p 278 ff. (b) Gilchrist, T.L. Heterocyclic Chemistry, 2nd ed:, Longman Scientific & Technical: Essex, 1992; p 204 ff. 130. Aspects of the Wittig and Horner-Wadsworth-Emmons reactions have been reviewed in: (a) Maryanoff, B.E.; Reitz, A.B. Chem. Rev. 1989,89, 863. (b) cf. Kelly, S.E. 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Corey, E.J.; Chaykovsky, M . / . Am. Chern. Soc. 1965,87,1345. 139. cf. Eisenbraun, E.J. Org. Synth. 1965,45,28. 140. Money, T.; Richardson, S.R.; Wong, M.K.C. Chern. Commun. 1996,667. 141. Bartlett, W.R.; Johnson, W.S.; Plummer, M.S.; Small, V.R., Jr. J. Org. Chern. 1990,55, 2215. 142. Kolaczkowski, L.; Reusch, W. J. Org. Chern. 1985,50,4766. 143. Woodward, R.B.; Patchett, A.A. ; Barton, D.H.R.; Ives, D.A.J.; Kelly, R.B. J. Chern. Soc. 1957,1131. 144. Woodward, R.B.; Sondheimer, F.; Taub, D.; Hensler, K.; McLamore, W . M . J. Am. Chern. Soc. 1952, 74, 4223; idem, ibid. 1951, 73, 3548; idem, ibid. 1951, 73, 3547; idem, ibid. 1951, 73, 2403. 145. van Tamelen, E.E.; Anderson, R.J. J. Am. Chern. Soc. 1972, 94, 8225 and references cited therein. 146. Corey, E.J.; Lee, J.; Liu, D.R. Tetrahedron Lett. 1994,35,9149. 147. Bull, J.R.; Bischofberger, K. / . Chern. Soc, Perkin Trans. 1 1983, 2723. 148. This proposal was made originally by Mr. (now Dr.) J. Andrew Clase, The University of British Columbia, Vancouver, Canada, 1988. 149. Further examples of the preparation and use of deuterium-labelled substrates for mechanistic studies may be found in References 46a and 72. 150- Trotter, J.; Rettig, S.J., The University of British Columbia, Vancouver, Canada, unpublished results. 151. Ferguson, C.G.; Money, T.; Pontillo, J.; Wong, M.K.C. submitted for publication in Tetrahedron, 152. Procedures for the purification of specific reagents and solvents may be found in: Pen-in, D.D.; Armarego, W.L.F. Purification of Laboratory Chemicals, 3rd ed.; Pergamon: Oxford, 1988. 153. White, C.T.; Heathcock, C H . / . Org. Chern. 1981,46,191. 154. (a) Kofron, W.G.; Baclawski, L .M. J.Org. Chern. 1976,47,1879. (b) Brown, H.C. Organic Syntheses via Boranes; John Wiley & Sons: New York, 1975; p 241 ff. 155. Still, W . G ; Kahn, M . ; Mitra, A. J. Org. Chern. 1978,43,2923. 220 156. The destruction and disposal of laboratory chemicals has been addressed in: (a) Armour, M. A. Hazardous Laboratory Chemicals Disposal Guide; CRC: Boca Raton, 1991. (b) Lunn, G. ; Sansone, E.B. Destruction of Hazardous Chemicals in the Laboratory; Wiley-Interscience: New York, 1990. (c) Prudent Practices for Disposal of Chemicals from Laboratories; Committee on Hazardous Substances in the Laboratory; Commission on Physical Sciences, Mathematics, and Resources; National Research Council; National Academy: Washington, 1983. 157. Aldrich Chemical Co.; Catalog /Handbook of Fine Chemicals; Aldrich: Milwaukee, Wl, 1994-1995. Appendix Supplementary Experimental Procedures 222 Appendix: Supplementary Experimental Procedures Preparation of Hydroxy-esters 161a and 161b Method 1: From Silyloxy-ester 162a H H 10 H 10 C0 2 Me 1. 0 3 ,CH 2 Cl2-MeOH(l: l ) , -78 0 C ^ j ^ C 0 2 M e + ^ j ^ C O . M e 2. NaBHj, -78 °C -> rt OTBDMS H 0 OTBDMS H ° OTBDMS 162a 161a 161b A stream of ozonized oxygen (-4% O3 in O 2 ) was bubbled into a solution of silyloxy-ester 162a (178.4 mg, 0.4086 mmol) in 1:1 C H 2 C l 2 - M e O H (10 mL) at -78 °C for 15 min. Excess ozone was purged with oxygen gas (~5 min). Solid sodium borohydride (54.1 mg, 1.43 m m o l ) 9 1 b - c was added in small portions over ~15 min while the reaction mixture was allowed to warm to room temperature (-20-25 min). The reaction mixture was then stirred for a further 1 h at room temperature after which it was poured into brine (20 mL). The organic layer was removed while the aqueous layer was extracted with dichloromethane (4 x 20 mL). The combined organic phases were washed with brine (3 x 100 mL), dried over anhydrous MgSC»4, and concentrated under reduced pressure to yield a pale yellow oil. Purification of the oil by flash column chromatography (30% EtOAc-pet. ether) yielded the minor hydroxy-ester diastereomer 161b (24.6 mg; 14%) and subsequently, the major hydroxy-ester diastereomer 161a (143.4 mg; 80%), both as colorless oils. Hydroxy-ester 161a 1H N M R (CDCI3, 400 MHz): 8 4.06-4.15 (m, 1H; simplifies to (dd, J = 8.5, 8.5 Hz) upon addition of D 2 0 ; H(4)), 3.55 (s, 3H; -C0 2 Me) , 3.51 (d, J = 9.1 Hz, 1H; H(6A)), 3.46 (d, J = 9.1 Hz, 1H; H(6B)), 2.19-2.30 (m, 2H; simplifies to (dd, J = 18.5, 8.2 Hz) upon addition of D 2 0 ; H(10A), -OH), 2.03-2.12 (m, 2H; H(10B), H(l)), 1.92-2.02 (m, 1H; H(3A)), 1.80-1.90 (m, 1H; H(2A)), 1.46-1.58 (m, 1H; H(2B)), 1.31-1.42 (m, 1H; H(3B)), 223 1.06 (s, 9 H ; Bu'), 0.83 (s, 3 H ; C ( 5 ) - C H 3 ) , 0.09 (s, 3 H ; -SiMe^Bu'), 0.02 (s, 3 H ; -SiMe?Bu'). IR (neat film): 3402 (VO_H). 2960,2859,1739 (vc=o), 1113 cm-l EIMS mlz (rel intensity): 285 ((M - OMe) + ; 0.2), 259 ((M - BuO) +; 4.7), 201 (1.5), 184 (0.8), 99 (100). Exact mass calcd for C i 2 H 2 3 0 4 S i [(M - Bu')+]: 259.1366, found 259.1372. Results of N O E experiment: Irradiation of the signal at 4.06-4.15 [H(4)] resulted in the enhancement of signal intensities at 2.19-2.30 [part of multiplet], 2.03-2.12 [part of multiplet], 1.80-1.90 [H(2A)], 1.06 [Bu'], 0.09 [-SiMe9Bu'1,0.02 r-SiMoBuH. Table A . l . Spectral Data from COSY Spectrum of Hydroxy-ester 161a. 400 MHz *H NMR Spectrum Signal Positions [8 (ppm)] Assign-ment COSY Correlations Signal Positions [8 (ppm)] Assign-ment 4.06-4.15 H(4) 2.19-2.30 (part of multiplet), 1.92-2.02, 1.31-1.42 - O H , H(3 A , 3B) 2.19-2.30 H(10A), - O H 4.06-4.15, 2.03-2.12 H(4), H(10B), H(l) 2.03-2.12 H(10B), H(l) 2.19-2.30 (part of multiplet), 1.80-1.90,1.46-1.58 H(10A), H(2A , 2B) 1.92-2.02 H(3A) 4.06-4.15,1.80-1.90,1.46-1.58, 1.31-1.42 H(4),H(3B), H(2 A ,2 B ) 1.80-1.90 H(2A) 2.03-2.12 (part of multiplet), 1.92-2.02,1.46-1.58,1.31-1.42 H(1),H(2B), H(3A , 3B) 1.46-1.58 H(2B) 2.03-2.12 (part of multiplet), 1.92-2.02,1.80-1.90,1.31-1.42 H(1),H(2A), H(3A , 3B) 1.31-1.42 H(3B) 4.06-4.15,1.92-2.02,1.80-1.90, 1.46-1.58 H(4),H(3A), H(2 A ,2 B ) 224 Hvdroxv-ester 161b 1H N M R ( C D C I 3 , 400 MHz): S 3.94-4.00 (m, 1H; simplifies to (dd, J = 7.5, 2.0 Hz) upon addition of D 2 0 ; H(4)), 3.62 (bs, 2H; H(6)), 3.58 (s, 3H; - C 0 2 M e ) , 3.18 (d, J = 3.5 Hz, 1H; exchanges with D 2 0 ; -OH), 2.42-2.55 (m, 1H; H(l)), 1.95-2.14 (m, 4H; H(10), H(3A), H(2 a)), 1.51-1.62 (m, 1H; H(3B)), 1.21-1.34 (m, 1H; H(2B)), 1.05 (s, 9H; BuO, 0.69 (s, 3H; C(5)-CH 3), 0.05 (s, 3H; -SiMe9BuO, -0.02 (s, 3H; -SiMe^BuO-IR (neat film): 3402 (VO_H), 2957, 2865, 1735 (v c =oX H02 cm"1 EIMS mlz (rel intensity): 285 ((M - OMe) + ; 1.9), 259 ((M - Bu0) + ; 14.5), 201 (4.1), 184 (2.0), 99 (100). Exact mass calcd for C i 2 H 2 3 0 4 S i [(M - Bu')+]: 259.1366, found 259.1369. Table A.2. Results of NOE Experiments for Hydroxy-ester 161b Proton Irradiated (ppm) Assignment NOE Correlations (ppm) Assignments* 3.94-4.00 H(4) 3.62,3.18,1.95-2.14 (part of multiplet), 1.51-1.62,0.69 H(6), - O H , H(3B), C(5)-CH 3 0.69 C(5)-CH 3 3.94-4.00, 3.62,1.95-2.14 (part of multiplet), 1.51-1.62, 1.21-1.34 H(4), H(6), H(3B), H(2B) *Only those protons that can be assigned unambiguously have been recorded. Method 2: From Keto-ester 163a H H 10 H 10 / - 4 ^ c 0 2 M e N a B H 4 , M e O H , 0 ° C / - 4 ^ C 0 2 M e , / ^ f ^ C 0 2 M e Vh " VTV rfr O T B D M S . | / I IH 0 O T B D M S H 0 O T B D M S 163a 161a 161b To a solution of keto-ester 163a (0.1003 g, 0.3189 mmol) in spectro grade methanol (10 mL) at 0 °C was added solid sodium borohydride (0.0145 g, 0.383 mmol). The clear, colorless 225 solution was stirred at 0 °C for 30 min, and then neutralized with 1 M HCl. The reaction mixture was diluted with Et20 (50 mL) and poured into brine. The organic phase was removed and the aqueous phase was extracted further with Et20 (2 x 50 mL). The combined extracts were washed with saturated aq. NaHCC«3 (2 x 100 mL) and brine (3 x 100 mL), dried over anhydrous MgS04, and concentrated to yield crude hydroxy-esters 161a and 161b as a viscous oil (0.9981 g). lH NMR analysis of the crude product revealed that the two hydroxy-esters 161a and 161b were present as a -3:1 mixture of diastereomers. Spectroscopic data for 161a and 162b were identical to those reported above. Attempted Intramolecular Aldol Condensation of Keto-aldehyde 198 Using 1% NaOH/Diethyl Ether.1 1 1 198 Keto-aldehyde 198 (9.9 mg, 0.039 mmol) was dissolved in reagent grade diethyl ether (-1.5 mL) and 1% aqueous sodium hydroxide (-1.0 mL) was added. The resulting two-phase mixture was stirred vigorously. No reaction was evident after 2 d, and the experiment was abandoned. 226 Attempted Potassium f-Butoxide Mediated Intramolecular Aldol Condensation of Keto-aldehyde 198.112 KOBu' , HOBu' O — 198 Potassium r-butoxide (62.2 mg, 0.554 mmol) was added to a solution of keto-aldehyde 198 (18.8 mg, 0.0736 mmol) in r-butanol (-0.7 m L ) . 1 1 2 The reaction mixture was stirred for 5 d, after which T L C revealed that the consumption of keto-aldehyde 198 was negligible; only a very faint spot with an R/ corresponding to that for hydroxy-ketone 199 could be detected. The experiment was abandoned. Attempted Lithium Iodide Mediated Intramolecular Aldol Condensation of Keto-aldehyde 198.H3 L i l , Et 20 To a solution of keto-aldehyde 198 (11.5 mg, 0.0452 mmol) in anhydrous diethyl ether (1.0 mL) was added anhydrous lithium iodide (15.1 mg, 0.113 mmol). 1 1 3 The mixture was stirred at room temperature and the progress of the reaction was monitored by T L C . After 48 h, no conversion of starting material to products was observed. The reaction was worked up as usual and the starting material was recovered (10.8 mg; 94% recovery) by flash column chromatography (75% Et20-pet. ether). Similar results were obtained when only 0.5 mL of anhydrous Et20 was used as solvent. 227 Attempted Diethylaluminum Ethoxide Mediated Intramolecular Aldol Condensation of Keto-aldehyde 198.114 198 Keto-aldehyde 198 (23.8 mg, 0.0936 mmol) was dissolved in dry dichloromethane (0.5 mL) and diethylaluminum ethoxide (0.58 mL, 1.6 M in toluene, 0.94 mmol) was added. 1 1 4 The colorless solution was stirred at (80 ± 5) °C for 3 d. Although all starting material (198) had been consumed, T L C analysis showed that the reaction mixture consisted of an inseparable mixture of products that were more polar than the starting material. Attempted p-ToIuenesulfonic Acid Mediated Intramolecular Aldol Condensation of Keto-aldehyde 198.115a p-Toluenesulfonic acid (-2.0 mg, 0.011 mmol) was added to a solution of keto-aldehyde 198 (14.1 mg, 0.0554 mmol) in dry benzene (10 mL) and the mixture was refluxed in a Dean-Stark apparatus. 1 1 5 3 After 3.5 d, T L C analysis revealed that significant decomposition of starting material into a complex mixture of products had occurred, although a spot with an Ry corresponding to that of ketal-enone 200 could also be observed. The reaction mixture was worked up through standard procedures. Flash column chromatography (75% Et20-pet. ether) of the crude product yielded a negligible amount of ketal-enone (3.1 mg, 21%). 228 Attempted Pyridinium p-Toluenesulfonate Mediated Intramolecular Aldol Condensation of Keto-aldehyde 198. 198 The PPTS-mediated aldol condensation of keto-aldehyde 198 was attempted via a procedure similar to that followed for the corresponding reaction involving p-toluenesulfonic acid (vide supra). No reaction was observed for 5 d, and the experiment was therefore abandoned. Attempted Boric Acid Mediated Intramolecular Aldol Condensation of Keto-aldehyde 198.H7 To a solution of keto-aldehyde 198 (15.2 mg, 0.0597 mmol) in dry benzene or toluene (5.0 mL) was added boric acid crystals (3.0 mg, 0.049 mmol). 1 1 7 The mixture was refluxed in a Dean-Stark apparatus for 5 d. The thin-layer chromatogram of the final product mixture showed an intense spot corresponding to starting material (198) and a very faint spot whose Ry coincided with that of authentic ketal-enone 200. The experiment was abandoned. Similar results were obtained when the amount of solvent was reduced (1.0 mL, 2.0 mL, or 3.0 mL) and no Dean-Stark apparatus was used. 229 Attempted Tetrabutylammonium Hydroxide Mediated Intramolecular Aldol Condensation of Keto-aldehyde 198. 200 201 A solution of keto-aldehyde (25.4 mg, 0.0998 mmol) and tetrabutylammonium hydroxide (0.35 mL, 40% solution in water, 0.50 mmol) in reagent grade dimethoxyethane (2.0 mL) was refluxed for 7 d. The reaction mixture was diluted with Et20 (50 mL), washed with water (2 x 50 mL) and brine (2 x 50 mL), dried over anhydrous MgSO"4, and concentrated under reduced pressure to yield a pale yellow oil. Purification of the oil by radial chromatography (1 mm plate; 20% Et20-pet. ether) yielded, in order of elution, ketal-enone 201 (16.1 mg; 82% based on recovered starting material), ketal-enone 200 (2.7 mg, 14% based on recovered starting material), and recovered keto-aldehyde 198 (4.2 mg). Spectroscopic data for ketal-enone 200 were identical to those reported on p. 161. Bicvclic Ketal-enone 201 1H N M R ( C D C I 3 , 400 MHz): 8 6.48 (d, J = 2.1 Hz, 1H; H(6)), 3.85-4.02 (m, 4H; -OCH2CH20-), 3.22 (qdd, J = 7.5, 7.5, 2.1 Hz, 1H; H(8)), 2.28-2.36 (m, 1H; H(l)), 2.28 (s, 3H; -C(0)CH 3 ) , 1.53-1.73 (m, 4H; H(2), H(3)), 1.13 (d, J = 7.5 Hz, 3H; C(8)-C H 3 ) , 1.05 (s, 3H; C(5)-CH3). IR (neat film): 2944,2912,2896,2864,1688 (vC=oX 1472,1408 cm-l Exact mass calcd for Ci4H 2 o0 3 : 236.1412, found 236.1420. 230 Table A.3. Spectral Data from COSY Spectrum of Ketal-enone 201. 400 MHz *H NMR Spectrum Signal Positions [8 (ppm)] Assign-ment COSY Correlations Signal Positions [8 (ppm)] Assignment 6.48 H(6) 3.22 H(8) 3.22 H(8) 6.48,2.28-2.36,1.13 H(6),H(1), C(8)-CH 3 2.28-2.36 H(l) 3.22,1.53-1.73 (part of multiplet) H(8), H(2) 1.53-1.73 H(2, 3) 2.28-2.36 H(l) 1.13 C(8)-CH3 3.22 H(8) Table A.4. Results of NOE Experiments for Ketal-enone 201. Proton Irradiated (ppm) Assignment NOE Correlations (ppm) Assignments* 6.48 H(6) 3.85^1.02, 2.28,1.05 -ketal, - C ( 0 ) C H 3 , C(5)-CH 3 3.22 H(8) 2.28-2.36,2.28,1.13 C(1),-C(0)CH 3 , C(8)-CH 3 1.13 C(8)-CH 3 6.48, 3.22,1.53-1.73,1.05 H(6), H(8), C(5)-CH 3 *Only those protons that can be assigned unambiguously have been recorded. 

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